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    Plasma interleukin-6 concentration for the diagnosis of sepsis in critically ill adults. Molano Franco Daniel,Arevalo-Rodriguez Ingrid,Roqué I Figuls Marta,Montero Oleas Nadia G,Nuvials Xavier,Zamora Javier The Cochrane database of systematic reviews BACKGROUND:The definition of sepsis has evolved over time, along with the clinical and scientific knowledge behind it. For years, sepsis was defined as a systemic inflammatory response syndrome (SIRS) in the presence of a documented or suspected infection. At present, sepsis is defined as a life-threatening organ dysfunction resulting from a dysregulated host response to infection. Even though sepsis is one of the leading causes of mortality in critically ill patients, and the World Health Organization (WHO) recognizes it as a healthcare priority, it still lacks an accurate diagnostic test. Determining the accuracy of interleukin-6 (IL-6) concentrations in plasma, which is proposed as a new biomarker for the diagnosis of sepsis, might be helpful to provide adequate and timely management of critically ill patients, and thus reduce the morbidity and mortality associated with this condition. OBJECTIVES:To determine the diagnostic accuracy of plasma interleukin-6 (IL-6) concentration for the diagnosis of bacterial sepsis in critically ill adults. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, LILACS, and Web of Science on 25 January 2019. We screened references in the included studies to identify additional studies. We did not apply any language restriction to the electronic searches. SELECTION CRITERIA:We included diagnostic accuracy studies enrolling critically ill adults aged 18 years or older under suspicion of sepsis during their hospitalization, where IL-6 concentrations were evaluated by serological measurement. DATA COLLECTION AND ANALYSIS:Two review authors independently screened the references to identify relevant studies and extracted data. We assessed the methodological quality of studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We estimated a summary receiver operating characteristic (SROC) curve by fitting a hierarchical summary ROC (HSROC) non-linear mixed model. We explored sources of heterogeneity using the HSROC model parameters. We conducted all analyses in the SAS statistical software package and R software. MAIN RESULTS:We included 23 studies (n = 4192) assessing the accuracy of IL-6 for the diagnosis of sepsis in critically ill adults. Twenty studies that were available as conference proceedings only are awaiting classification. The included participants were heterogeneous in terms of their distribution of age, gender, main diagnosis, setting, country, positivity threshold, sepsis criteria, year of publication, and origin of infection, among other factors. Prevalence of sepsis greatly varied across studies, ranging from 12% to 78%. We considered all studies to be at high risk of bias due to issues related to the index test domain in QUADAS-2. The SROC curve showed a great dispersion in individual studies accuracy estimates (21 studies, 3650 adult patients), therefore the considerable heterogeneity in the collected data prevented us from calculating formal accuracy estimates. Using a fixed prevalence of sepsis of 50% and a fixed specificity of 74%, we found a sensitivity of 66% (95% confidence interval 60 to 72). If we test a cohort 1000 adult patients under suspicion of sepsis with IL-6, we will find that 330 patients would receive appropriate and timely antibiotic therapy, while 130 patients would be wrongly considered to have sepsis. In addition, 370 out of 1000 patients would avoid unnecessary antibiotic therapy, and 170 patients would have been undiagnosed of sepsis. This numerical approach should be interpreted with caution due to the limitations described above. AUTHORS' CONCLUSIONS:Our evidence assessment of plasma interleukin-6 concentrations for the diagnosis of sepsis in critically ill adults reveals several limitations. High heterogeneity of collected evidence regarding the main diagnosis, setting, country, positivity threshold, sepsis criteria, year of publication, and the origin of infection, among other factors, along with the potential number of misclassifications, remain significant constraints for its implementation. The 20 conference proceedings assessed as studies awaiting classification may alter the conclusions of the review once they are fully published and evaluated. Further studies about the accuracy of interleukin-6 for the diagnosis of sepsis in adults that apply rigorous methodology for conducting diagnostic test accuracy studies are needed. The conclusions of the review will likely change once the 20 studies pending publication are fully published and included. 10.1002/14651858.CD011811.pub2
    Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II-Induced Microvascular Dysfunction. Senchenkova Elena Y,Russell Janice,Yildirim Alper,Granger D Neil,Gavins Felicity N E Hypertension (Dallas, Tex. : 1979) Hypertension is an established risk factor for subsequent cardiovascular diseases, with Ang II (angiotensin II) playing a major role in mediating thrombotic and inflammatory abnormalities. Although T cells and IL-6 (interleukin-6) play an important role in adaptive immune responses, little is known about their role(s) in the thromboinflammatory responses associated with Ang II. Here we show using intravital microscopy coupled with the light/dye injury model that Rag-1 deficient (Rag-1) and IL-6 deficient (IL-6) mice are afforded protection against Ang II-induced thrombosis. Blocking IL-6 receptors (using CD126 and gp130 antibodies) significantly diminished Ang II-mediated thrombosis and inflammatory cell recruitment in mice. Furthermore, the adoptive transfer of IL-6-derived T cells into Rag-1 mice failed to accelerate Ang II-induced thrombosis compared with Rag-1 mice reconstituted with wild-type-derived T cells, suggesting T cell IL-6 mediates the thrombotic abnormalities associated Ang II hypertension. Interestingly, adoptive transfer of WT T cells into Rag-1/Ang II mice resulted in increased numbers of immature platelets, which constitutes a more active platelet population, that is, prothrombotic and proinflammatory. To translate our in vivo findings, we used clinical samples to demonstrate that IL-6 also predisposes platelets to an interaction with collagen receptors, thereby increasing the propensity for platelets to aggregate and cause thrombosis. In summary, we provide compelling evidence for the involvement of IL-6, IL-6R, and T-cell-dependent IL-6 signaling in Ang II-induced thromboinflammation, which may provide new therapeutic possibilities for drug discovery programs for the management of hypertension. 10.1161/HYPERTENSIONAHA.118.12286
    Blocking interleukin-6 trans-signaling protects against renal fibrosis by suppressing STAT3 activation. Chen Wei,Yuan Hui,Cao Wenmin,Wang Tianwei,Chen Wei,Yu Hang,Fu Yao,Jiang Bo,Zhou Hong,Guo Hongqian,Zhao Xiaozhi Theranostics : Renal fibrosis is the terminal manifestation of chronic and irreversible renal disease. Effective therapies other than dialysis are extremely limited. In this study, we investigated the potential effects of targeting elevated interleukin-6 (IL-6) levels in the treatment of renal fibrosis. : Fc-gp130 was used to specifically block IL-6 trans-signaling. Unilateral ureteral occlusion (UUO) and ischemia reperfusion (IR) mouse models were constructed to investigate the therapeutic effect of Fc-gp130 on renal fibrosis. The role of IL-6 trans-signaling and phosphorylation of signal transducer and activator of transcription (STAT) 3 in regulating fibroblast accumulation and extracellular matrix protein deposition were evaluated in cell experiments and mouse models. : The kidneys of mice with UUO were found to have elevated soluble IL-6 receptor (sIL-6R) levels in the progression of fibrosis. Fc-gp130 attenuated renal fibrosis in mice, as evidenced by reductions in tubular atrophy and the production of extracellular matrix protein. Blockade of IL-6 trans-signaling with Fc-gp130 also reduced inflammation levels, immune cell infiltration, and profibrotic cytokines expression in renal tissue, with decreased STAT3 phosphorylation and reduced fibroblast accumulation in the renal tissue. In vitro, Fc-gp130 also reduced the phosphorylation of STAT3 induced by transforming growth factor (TGF)-β1 in fibroblasts. Furthermore, the therapeutic effect of Fc-gp130 was confirmed in a model of acute kidney injury-chronic kidney disease. : Overall, IL-6 trans-signaling may contribute to crucial events in the development of renal fibrosis, and the targeting of IL-6 trans-signaling by Fc-gp130 may provide a novel therapeutic strategy for the treatment of renal fibrosis. 10.7150/thno.32352
    HIMF (Hypoxia-Induced Mitogenic Factor)-IL (Interleukin)-6 Signaling Mediates Cardiomyocyte-Fibroblast Crosstalk to Promote Cardiac Hypertrophy and Fibrosis. Kumar Santosh,Wang Gang,Zheng Na,Cheng Wanwen,Ouyang Kunfu,Lin Hairuo,Liao Yulin,Liu Jie Hypertension (Dallas, Tex. : 1979) HIMF (hypoxia-induced mitogenic factor) is a secreted proinflammatory cytokine with a critical role in cardiac hypertrophy development. Loss of HIMF attenuates transverse aortic constriction-induced cardiac hypertrophy and fibrosis, but the underlying mechanisms are unknown. We show that IL (interleukin)-6 production increases following transverse aortic constriction in wild-type mice; this effect is inhibited in HIMF gene knockout ( Himf) mice. IL-6 production also increases in cultured cardiac myocytes overexpressing HIMF and neutralizing IL-6 with an anti-IL-6 antibody prohibits HIMF-induced cardiomyocyte hypertrophy. HIMF expression in cardiac fibroblasts cannot be stimulated by transverse aortic constriction or exposure to prohypertrophic factors, including phenylephrine, Ang II (angiotensin II), TGF (transform growth factor)-β, and hypoxia. However, conditioned medium from cardiomyocytes overexpressing HIMF can increase IL-6 production, and cardiac fibroblast proliferation, migration, and myofibroblast differentiation to a similar level as exposure to exogenous rHIMF (recombinant HIMF). Again, neutralizing IL-6 prevented cardiac fibroblasts activation. Finally, the MAPK (mitogen-activated protein kinase) and CaMKII (Ca/calmodulin-dependent protein kinase II)-STAT3 (signal transducers and activators of transcription 3) pathways are activated in HIMF-overexpressing cardiomyocytes and rHIMF-stimulated cardiac fibroblasts; this effect can be inhibited on neutralizing IL-6. These data support that HIMF induces cardiac fibrosis via a cardiomyocyte-to-fibroblast paracrine effect. IL-6 is a downstream signal of HIMF and has a central role in cardiomyocyte hypertrophy and myocardial fibrosis that is mediated by activating the MAPK and CaMKII-STAT3 pathways. 10.1161/HYPERTENSIONAHA.118.12267
    Inflammatory and oxidative injury is induced in cardiac and pulmonary tissue following fipronil exposure in Japanese quail: mRNA expression of the genes encoding interleukin 6, nuclear factor kappa B, and tumor necrosis factor-alpha. Khalil Samah R,Mohammed Wafaa A,Zaglool Asmaa W,Elhady Walaa M,Farag Mayada R,El Sayed Shafika A M Environmental pollution (Barking, Essex : 1987) The phenylpyrazole insecticide, fipronil, isused for the eradication of insects in agriculture, which also exposes various non-target groups such as birds and animals. Our aim was to assess the cardiac and pulmonary consequences of sub-acute administration of fipronil (∕ LD; 2.26 mg/kg) in the Japanese quail for fifteen days and to determine the tissue recovery over a period of 60 days. Fipronil exposure led to a significant decrease in the body weight of the treated birds. Its exposure also induced cardiac and pulmonary damage of varying degrees. Fipronil increased the lipid peroxide (LPO) and nitric oxide (NO) contents as well as indices of tissue injury in the serum of exposed birds. Furthermore, it decreased the antioxidant indices in both the organs. Most of these changes gradually reversed and the histological changes, particularly of the heart, reversed completely by day-60 of recovery. Furthermore, alterations in the mRNA gene expressions of Nuclear factor kappa B (NF-κB), Interleukin 6 (IL-6), and Tumor necrosis factor-alpha (TNF-α) were monitored by quantitative polymerase chain reaction (RT-PCR). In both the tissues, a significant up-regulation of the transcripts was recorded after fipronil administration, which was reversed during the recovery period in the heart tissue except for TNF-α, while the transcripts in the lung tissue declined non-significantly. This study showed that the exposure of Japanese quail to fipronil has a profound negative impact on heart and lung including oxidative injury and tissue inflammation. Fipronil can induce the activity of NF-κB inflammatory -signaling pathway that play a role in the associated tissue inflammation. Although most of the cardiac changes could be reversed after a recovery period of sixty days, the pulmonary changes did not reverse much. 10.1016/j.envpol.2019.05.012
    The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Markousis-Mavrogenis George,Tromp Jasper,Ouwerkerk Wouter,Devalaraja Matt,Anker Stefan D,Cleland John G,Dickstein Kenneth,Filippatos Gerasimos S,van der Harst Pim,Lang Chim C,Metra Marco,Ng Leong L,Ponikowski Piotr,Samani Nilesh J,Zannad Faiez,Zwinderman Aeilko H,Hillege Hans L,van Veldhuisen Dirk J,Kakkar Rahul,Voors Adriaan A,van der Meer Peter European journal of heart failure AIMS:Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)-α were largely unsuccessful. Interleukin (IL)-6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL-6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. METHODS AND RESULTS:Interleukin-6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT-CHF cohort. The primary outcome was all-cause mortality and HF hospitalization during 2 years, with all-cause, cardiovascular (CV), and non-CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL-6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N-terminal pro-brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF-α/IL-1-related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL-6 levels. IL-6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11-1.21), P < 0.001], all-cause mortality [1.22 (1.16-1.29), P < 0.001] and CV as well as non-CV mortality [1.16 (1.09-1.24), P < 0.001; 1.31 (1.18-1.45), P < 0.001], but did not improve discrimination in previously published risk models. CONCLUSIONS:In a large, heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL-6 as a potential therapeutic target in specific HF subpopulations. 10.1002/ejhf.1482
    Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. Spencer Sarah,Köstel Bal Sevgi,Egner William,Lango Allen Hana,Raza Syed I,Ma Chi A,Gürel Meltem,Zhang Yuan,Sun Guangping,Sabroe Ruth A,Greene Daniel,Rae William,Shahin Tala,Kania Katarzyna,Ardy Rico Chandra,Thian Marini,Staples Emily,Pecchia-Bekkum Annika,Worrall William P M,Stephens Jonathan,Brown Matthew,Tuna Salih,York Melanie,Shackley Fiona,Kerrin Diarmuid,Sargur Ravishankar,Condliffe Alison,Tipu Hamid Nawaz,Kuehn Hye Sun,Rosenzweig Sergio D,Turro Ernest,Tavaré Simon,Thrasher Adrian J,Jodrell Duncan Ian,Smith Kenneth G C,Boztug Kaan,Milner Joshua D,Thaventhiran James E D The Journal of experimental medicine IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by We describe two patients with homozygous mutations in who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in , and genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R. 10.1084/jem.20190344
    Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin-6 Receptor-Dependent Mechanism: Cardiac Analysis of a Double-Blind Randomized Controlled Clinical Trial in Abdominally Obese Humans. Christensen Regitse Højgaard,Lehrskov Louise Lang,Wedell-Neergaard Anne-Sophie,Legaard Grit Elster,Ried-Larsen Mathias,Karstoft Kristian,Krogh-Madsen Rikke,Pedersen Bente Klarlund,Ellingsgaard Helga,Rosenmeier Jaya Birgitte Circulation 10.1161/CIRCULATIONAHA.119.042287
    Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis. Bick Alexander G,Pirruccello James P,Griffin Gabriel K,Gupta Namrata,Gabriel Stacey,Saleheen Danish,Libby Peter,Kathiresan Sekar,Natarajan Pradeep Circulation BACKGROUND:Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as or . In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk. METHODS:We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with or CHIP. We used the p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by p.Asp358Ala. RESULTS:We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04-1.56], =0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21-2.09], <0.001). p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29-0.73], <0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89-1.01], =0.08; =0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by p.Asp358Ala (=0.036). CONCLUSIONS:CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk. 10.1161/CIRCULATIONAHA.119.044362
    Regulation of adipose tissue inflammation by interleukin 6. Han Myoung Sook,White Alexis,Perry Rachel J,Camporez Joao-Paulo,Hidalgo Juan,Shulman Gerald I,Davis Roger J Proceedings of the National Academy of Sciences of the United States of America Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear. We tested the role of specific cells using a mouse model with conditional expression of the gene. We found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. These opposite actions were associated with a switch of IL6 signaling from a canonical mode (myeloid cells) to a noncanonical -signaling mode (adipocytes and muscle) with increased expression of the ADAM10/17 metalloprotease that promotes -signaling by the soluble IL6 receptor α. Collectively, these data demonstrate that the source of IL6 production plays a major role in the physiological regulation of metabolism. 10.1073/pnas.1920004117
    IL (Interleukin)-6 Contributes to Deep Vein Thrombosis and Is Negatively Regulated by miR-338-5p. Zhang Yunhong,Zhang Zhen,Wei Ran,Miao Xiuming,Sun Shangwen,Liang Gang,Chu Chu,Zhao Lin,Zhu Xiaoxiao,Guo Qiang,Wang Bin,Li Xia Arteriosclerosis, thrombosis, and vascular biology OBJECTIVE:Deep venous thrombosis (DVT), one of the most common venous thromboembolic disorders, is closely linked with pulmonary embolism and post-thrombotic syndrome, both of which have a high mortality. However, the factors that trigger DVT formation are still largely unknown. Elevated expression of IL (interleukin)-6-an important inflammatory cytokine-has been linked with DVT formation. However, the molecular mechanisms leading to the elevated IL-6 in DVT remain unclear. Here, we proposed that epigenetic modification of IL-6 at the post-transcriptional level may be a crucial trigger for IL-6 upregulation in DVT. Approach and Results: To explore the association between microRNAs and IL-6 in DVT, we performed microRNA microarray analysis and experiments both in vitro and in vivo. Microarray and quantitative real-time polymerase chain reaction results showed that IL-6 expression was increased while miR-338-5p level was decreased substantially in peripheral blood mononuclear cells of patients with DVT, and there was significant negative correlation between miR-338-5p and IL-6. Experiments in vitro showed that overexpressed miR-338-5p reduced IL-6 expression, while miR-338-5p knockdown increased IL-6 expression. Moreover, our in vivo study found that mice with anti-IL-6 antibody or agomiR-338-5p delivery resulted in decreased IL-6 expression and alleviated DVT formation, whereas antagomiR-338-5p acted inversely. Most of miR-338-5p was found located in cytoplasm by fluorescence in situ hybridization. Dual-luciferase reporter assay identified direct binding between miR-338-5p and . CONCLUSIONS:Our results suggest that decreased miR-338-5p promotes DVT formation by increasing IL-6 expression. 10.1161/ATVBAHA.119.313137
    Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension. The European respiratory journal The pro-inflammatory cytokine interleukin (IL)-6 has been associated with outcomes in small pulmonary arterial hypertension (PAH) cohorts composed largely of patients with severe idiopathic PAH (IPAH). It is unclear whether IL-6 is a marker of critical illness or a mechanistic biomarker of pulmonary vascular remodelling. We hypothesised that IL-6 is produced by pulmonary vascular cells and sought to explore IL-6 associations with phenotypes and outcomes across diverse subtypes in a large PAH cohort.IL-6 protein and gene expression levels were measured in cultured pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) from PAH patients and healthy controls. Serum IL-6 was measured in 2017 well-characterised PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analysed using regression models.Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (p<0.001), while there was no difference in IL-6 between cell types in controls. Serum IL-6 was highest in PAH related to portal hypertension and connective tissue diseases (CTD-PAH). In multivariable modelling, serum IL-6 was associated with survival in the overall cohort (hazard ratio 1.22, 95% CI 1.08-1.38; p<0.01) and in IPAH, but not in CTD-PAH. IL-6 remained associated with survival in low-risk subgroups of subjects with mild disease.IL-6 is released from PASMCs, and circulating IL-6 is associated with specific clinical phenotypes and outcomes in various PAH subgroups, including subjects with less severe disease. IL-6 is a mechanistic biomarker, and thus a potential therapeutic target, in certain PAH subgroups. 10.1183/13993003.01761-2019
    Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Ridker Paul M,MacFadyen Jean G,Thuren Tom,Libby Peter European heart journal AIMS:The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis. METHODS AND RESULTS:Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1β inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values <0.001). By contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects <1%, all P-values > 0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3-29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42% increase in risk (95% CI 26-59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6. CONCLUSION:There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with canakinumab These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors). CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT01327846. 10.1093/eurheartj/ehz542
    Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11. Metcalfe Riley D,Putoczki Tracy L,Griffin Michael D W Frontiers in immunology Cytokines are small signaling proteins that have central roles in inflammation and cell survival. In the half-century since the discovery of the first cytokines, the interferons, over fifty cytokines have been identified. Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use. Here we outline our current knowledge of the structural mechanism of signaling by the IL-6 family of cytokines. We discuss how this knowledge allows us to understand the mechanism of action of currently available inhibitors targeting IL-6 family cytokine signaling, and most importantly how it allows for improved opportunities to pharmacologically disrupt cytokine signaling. We focus specifically on the need to develop and understand inhibitors that disrupt IL-11 signaling. 10.3389/fimmu.2020.01424
    Interleukin-6 trans-signaling inhibition prevents oxidative stress in a mouse model of early diabetic retinopathy. Robinson Rebekah,Srinivasan Mukund,Shanmugam Arul,Ward Alexander,Ganapathy Veena,Bloom Justin,Sharma Ashok,Sharma Shruti Redox biology PURPOSE:Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of visual disability and blindness in diabetic patients. Chronic hyperglycemia leads to increased oxidative stress and inflammation in the retina, resulting in microvascular damage. Our recent in vitro studies have demonstrated that inhibition of interleukin-6 (IL-6) trans-signaling significantly reduces oxidative stress in retinal endothelial cells. The purpose of this study was to further explore the relationship between IL-6 trans-signaling and oxidative stress using a streptozotocin (STZ) induced mouse model of early diabetic retinopathy. METHODS:Diabetes was induced in eight week-old male C57BL/6J mice using STZ injections. sgp130Fc (mouse sgp130Fc protein) treatment was used for inhibition of IL-6 trans-signaling. Studies were conducted to evaluate the effects of IL-6 trans-signaling on oxidative balance at the systemic and retinal level. RESULTS:Decreased antioxidant capacity and increased oxidative stress was observed in diabetic mice, which returned to near-normal levels with sgp130Fc treatment. Similarly, superoxide levels, lipid peroxidation, and markers of oxidative DNA damage were increased in the diabetic retina, and these effects were abrogated by sgp130Fc treatment. Inhibition of IL-6 trans-signaling also restored normal expression of catalase and endothelial nitric oxide synthase in mouse retinas. CONCLUSIONS:Inhibition of IL-6 trans-signaling significantly reduces diabetes-induced oxidative damage at the systemic level and in the retina. These findings provide further evidence for the role of IL-6 trans-signaling in diabetes-mediated oxidative stress. 10.1016/j.redox.2020.101574
    Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial. Ridker Paul M,MacFadyen Jean G,Glynn Robert J,Bradwin Gary,Hasan Ahmed A,Rifai Nader European heart journal AIMS:In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary therapy for atherosclerosis has altered these relationships is unknown yet has major implications for future drug development. METHODS AND RESULTS:Interleukin-6, hsCRP, and LDLC were measured at baseline in up to 4168 North American patients enrolled in the contemporary Cardiovascular Inflammation Reduction Trial with prior myocardial infarction or multivessel coronary disease who additionally had diabetes or metabolic syndrome and were followed for a period of up to 5 years for incident major recurrent cardiovascular events and all-cause mortality. Three-quarters of the cohort were previously revascularized and the great majority was taking statins, angiotensin blocking agents, beta-blockers, and antithrombotic agents. Participants were randomly allocated to low-dose methotrexate 15 mg weekly or to placebo. Randomized use of methotrexate had no effect on event rates nor plasma levels of IL-6, hsCRP, or LDL over time. Yet, baseline levels of IL-6, hsCRP, and LDLC were all predictors of major recurrent cardiovascular events; adjusted hazard ratios [HR; 95% confidence interval (CI)] for the lowest to highest baseline quartiles of IL-6 were 1.0 (referent), 1.66 (1.18-2.35), 1.92 (1.36-2.70), and 2.11 (1.49-2.99; P < 0.0001), while adjusted HRs for increasing quartiles of hsCRP were 1.0 (referent), 1.28 (0.92-1.79), 1.73 (1.25-2.38), and 1.79 (1.28-2.50; P < 0.0001) and adjusted HRs for increasing quartiles of LDLC were 1.0 (referent), 1.12 (0.78-1.62), 1.25 (0.87-1.79), and 2.38 (1.72-3.30; P < 0.0001). Effect estimates were not statistically different in these analyses for comparisons between IL-6, hsCRP, or LDLC, although IL-6 was the strongest predictor of all-cause mortality. The highest absolute risks were observed among those with elevated levels of both cholesterol and inflammation [HR 6.4 (95% CI 2.9-14.1) for those in the top quartiles of baseline IL-6 and LDLC, HR 4.9 (95% CI 2.6-9.4) for those in the top quartiles of baseline hsCRP and LDLC, both P < 0.0001]. CONCLUSION:Despite aggressive contemporary secondary prevention efforts, the relationships between inflammation, cholesterol, and cardiovascular risk are largely unchanged from those described two decades ago. These data are consistent with the hypothesis that future treatments for atherosclerosis may require a combination of inflammation inhibition and additional cholesterol reduction. CLINICAL TRIAL:ClinicalTrials.gov NCT01594333. 10.1093/eurheartj/ehaa160
    Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency. Werner-Klein Melanie,Grujovic Ana,Irlbeck Christoph,Obradović Milan,Hoffmann Martin,Koerkel-Qu Huiqin,Lu Xin,Treitschke Steffi,Köstler Cäcilia,Botteron Catherine,Weidele Kathrin,Werno Christian,Polzer Bernhard,Kirsch Stefan,Gužvić Miodrag,Warfsmann Jens,Honarnejad Kamran,Czyz Zbigniew,Feliciello Giancarlo,Blochberger Isabell,Grunewald Sandra,Schneider Elisabeth,Haunschild Gundula,Patwary Nina,Guetter Severin,Huber Sandra,Rack Brigitte,Harbeck Nadia,Buchholz Stefan,Rümmele Petra,Heine Norbert,Rose-John Stefan,Klein Christoph A Nature communications Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals. 10.1038/s41467-020-18701-4
    Targeting Interleukin-1 and Interleukin-6: The Time Has Come to Aggressively Address Residual Inflammatory Risk. Ridker Paul M Journal of the American College of Cardiology 10.1016/j.jacc.2020.08.052
    Interleukin-6 neutralization ameliorates symptoms in prematurely aged mice. Squarzoni Stefano,Schena Elisa,Sabatelli Patrizia,Mattioli Elisabetta,Capanni Cristina,Cenni Vittoria,D'Apice Maria Rosaria,Andrenacci Davide,Sarli Giuseppe,Pellegrino Valeria,Festa Anna,Baruffaldi Fabio,Storci Gianluca,Bonafè Massimiliano,Barboni Catia,Sanapo Mara,Zaghini Anna,Lattanzi Giovanna Aging cell Hutchinson-Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and Lmna progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders. 10.1111/acel.13285
    Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension. Florentin Jonathan,Zhao Jingsi,Tai Yi-Yin,Vasamsetti Sathish Babu,O'Neil Scott P,Kumar Rahul,Arunkumar Anagha,Watson Annie,Sembrat John,Bullock Grant C,Sanders Linda,Kassa Biruk,Rojas Mauricio,Graham Brian B,Chan Stephen Y,Dutta Partha Cellular & molecular immunology Myeloid cells, such as neutrophils, are produced in the bone marrow in high quantities and are important in the pathogenesis of vascular diseases such as pulmonary hypertension (PH). Although neutrophil recruitment into sites of inflammation has been well studied, the mechanisms of neutrophil egress from the bone marrow are not well understood. Using computational flow cytometry, we observed increased neutrophils in the lungs of patients and mice with PH. Moreover, we found elevated levels of IL-6 in the blood and lungs of patients and mice with PH. We observed that transgenic mice overexpressing Il-6 in the lungs displayed elevated neutrophil egress from the bone marrow and exaggerated neutrophil recruitment to the lungs, resulting in exacerbated pulmonary vascular remodeling, and dysfunctional hemodynamics. Mechanistically, we found that IL-6-induced neutrophil egress from the bone marrow was dependent on interferon regulatory factor 4 (IRF-4)-mediated CXCR1 expression in neutrophils. Consequently, Cxcr1 genetic deficiency in hematopoietic cells in Il-6-transgenic mice significantly reduced neutrophil egress from bone marrow and decreased neutrophil counts in the lungs, thus ameliorating pulmonary remodeling and hemodynamics. In summary, these findings define a novel mechanism of IL-6-induced neutrophil egress from the bone marrow and reveal a new therapeutic target to curtail neutrophil-mediated inflammation in pulmonary vascular disease. 10.1038/s41423-020-00608-1
    The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells. Yousif Ashraf S,Ronsard Larance,Shah Pankaj,Omatsu Tatsushi,Sangesland Maya,Bracamonte Moreno Thalia,Lam Evan C,Vrbanac Vladimir D,Balazs Alejandro B,Reinecker Hans-Christian,Lingwood Daniel Immunity The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions. 10.1016/j.immuni.2020.12.001
    Association of Interleukin-6 Levels and Futile Reperfusion After Mechanical Thrombectomy. Mechtouff Laura,Bochaton Thomas,Paccalet Alexandre,Da Silva Claire Crola,Buisson Marielle,Amaz Camille,Derex Laurent,Ong Elodie,Berthezene Yves,Eker Omer Faruk,Dufay Nathalie,Mewton Nathan,Ovize Michel,Cho Tae-Hee,Nighoghossian Norbert Neurology OBJECTIVE:To assess whether interleukin-6 (IL-6) level is a marker of futile reperfusion in patients with acute ischemic stroke (AIS) with large vessel occlusion treated with mechanical thrombectomy (MT). METHODS:The Cohort of Patients to Identify Biological and Imaging Markers of Cardiovascular Outcomes in Stroke (HIBISCUS-STROKE) includes patients with AIS treated with MT after MRI. We performed a sequential assessment of IL-6 (admission, 6 hours, 24 hours, 48 hours and 3 months from admission). Among patients with successful reperfusion (Thrombolysis in Cerebral Infarction scale 2b/3), reperfusion was considered effective if 3-month modified Rankin Scale (mRS) score was 0 to 2 and futile if 3-month mRS score was 3 to 6. Our model was adjusted for the main confounding variables. RESULTS:One hundred sixty-four patients represent the study population. One hundred thirty-three patients had successful reperfusion (81.1%), while in 46 (34.6%), reperfusion was classified as futile. In single-variable analyses, high IL-6 levels at 6, 24, and 48 hours in combination with a higher age, a prestroke mRS score >2, a history of hypertension or diabetes, lack of current smoking, a higher baseline NIH Stroke Scale score, the absence of associated intravenous thrombolysis, an intracranial internal carotid artery or a tandem occlusion, and an increased infarct growth were associated with futile reperfusion. After multivariable analyses, a high IL-6 level at 24 hours (odds ratio 6.15, 95% confidence interval 1.71-22.10) remained associated with futile reperfusion. CONCLUSIONS:IL-6 is a marker of futile reperfusion in the setting of MT. 10.1212/WNL.0000000000011268
    Genetically Downregulated Interleukin-6 Signaling Is Associated With a Favorable Cardiometabolic Profile: A Phenome-Wide Association Study. Georgakis Marios K,Malik Rainer,Li Xue,Gill Dipender,Levin Michael G,Vy Ha My T,Judy Renae,Ritchie Marylyn,Verma Shefali S, ,Nadkarni Girish N,Damrauer Scott M,Theodoratou Evropi,Dichgans Martin Circulation 10.1161/CIRCULATIONAHA.120.052604
    Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. ,Gordon Anthony C,Mouncey Paul R,Al-Beidh Farah,Rowan Kathryn M,Nichol Alistair D,Arabi Yaseen M,Annane Djillali,Beane Abi,van Bentum-Puijk Wilma,Berry Lindsay R,Bhimani Zahra,Bonten Marc J M,Bradbury Charlotte A,Brunkhorst Frank M,Buzgau Adrian,Cheng Allen C,Detry Michelle A,Duffy Eamon J,Estcourt Lise J,Fitzgerald Mark,Goossens Herman,Haniffa Rashan,Higgins Alisa M,Hills Thomas E,Horvat Christopher M,Lamontagne Francois,Lawler Patrick R,Leavis Helen L,Linstrum Kelsey M,Litton Edward,Lorenzi Elizabeth,Marshall John C,Mayr Florian B,McAuley Daniel F,McGlothlin Anna,McGuinness Shay P,McVerry Bryan J,Montgomery Stephanie K,Morpeth Susan C,Murthy Srinivas,Orr Katrina,Parke Rachael L,Parker Jane C,Patanwala Asad E,Pettilä Ville,Rademaker Emma,Santos Marlene S,Saunders Christina T,Seymour Christopher W,Shankar-Hari Manu,Sligl Wendy I,Turgeon Alexis F,Turner Anne M,van de Veerdonk Frank L,Zarychanski Ryan,Green Cameron,Lewis Roger J,Angus Derek C,McArthur Colin J,Berry Scott,Webb Steve A,Derde Lennie P G The New England journal of medicine BACKGROUND:The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS:We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS:Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS:In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.). 10.1056/NEJMoa2100433
    Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction. Broch Kaspar,Anstensrud Anne Kristine,Woxholt Sindre,Sharma Kapil,Tøllefsen Ingvild Maria,Bendz Bjørn,Aakhus Svend,Ueland Thor,Amundsen Brage Høyem,Damås Jan Kristian,Berg Erlend Sturle,Bjørkelund Elisabeth,Bendz Christina,Hopp Einar,Kleveland Ola,Stensæth Knut Haakon,Opdahl Anders,Kløw Nils-Einar,Seljeflot Ingebjørg,Andersen Geir Øystein,Wiseth Rune,Aukrust Pål,Gullestad Lars Journal of the American College of Cardiology BACKGROUND:Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. OBJECTIVES:This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. METHODS:The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. RESULTS:We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. CONCLUSIONS:Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703). 10.1016/j.jacc.2021.02.049
    Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction. George Marc Jonathan,Jasmin Nur Hayati,Cummings Valerie Taylor,Richard-Loendt Angela,Launchbury Francesca,Woollard Kevin,Turner-Stokes Tabitha,Garcia Diaz Ana Isabel,Lythgoe Mark,Stuckey Daniel James,Hingorani Aroon Dinesh,Gilroy Derek William JACC. Basic to translational science Interleukin (IL)-6 is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti-IL-6 antibodies (Abs) result in panantagonism. In a rat model of reperfused MI, sgp130Fc, but not anti-IL-6-Ab, attenuated neutrophil and macrophage infiltration into the myocardium, reduced infarct size, and preserved cardiac function 28 days after MI. These data demonstrate the efficacy of exclusive IL-6 trans-signaling blockade and support further investigation of sgp130Fc as a potential novel therapy in MI. 10.1016/j.jacbts.2021.01.013
    Inhibiting Interleukin-6 to Reduce Cardiovascular Event Rates: A Next Step for Atherothrombosis Treatment and Prevention. Ridker Paul M Journal of the American College of Cardiology 10.1016/j.jacc.2021.02.060
    Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, Placebo-Controlled, Single-Center, Randomized, Clinical Trial. Meyer Martin Abild Stengaard,Wiberg Sebastian,Grand Johannes,Meyer Anna Sina Pettersson,Obling Laust Emil Roelsgaard,Frydland Martin,Thomsen Jakob Hartvig,Josiassen Jakob,Møller Jacob Eifer,Kjaergaard Jesper,Hassager Christian Circulation BACKGROUND:Patients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post-cardiac arrest syndrome. Systemic inflammation constitutes a major component of post-cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post-cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post-cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury. METHODS:Eighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis. RESULTS:The primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, <0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: -84% [-90%; -76%] and -34% [-46%; -19%], respectively, both <0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: -36% [-54%; -11%] and -38% [-53%; -19%], respectively, both <0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: -65% [-80%; -41%], <0.001. There were no differences in survival or neurological outcome. CONCLUSIONS:Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015. 10.1161/CIRCULATIONAHA.120.053318
    Interleukin-6: A novel biomarker for monoclonal antibody and chemotherapy-associated hypersensitivity confirms a cytokine release syndrome phenotype-endotype association. Jakubovic Baruch D,Sanchez-Sanchez Soledad,Hamadi Sahar,Lynch Donna-Marie,Castells Mariana Allergy 10.1111/all.14644
    Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease. Ridker Paul M,Rane Manas Circulation research IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need. 10.1161/CIRCRESAHA.121.319077
    Natural Glycoforms of Human Interleukin 6 Show Atypical Plasma Clearance. Reif Andreas,Lam Kevin,Weidler Sascha,Lott Marie,Boos Irene,Lokau Juliane,Bretscher Christian,Mönnich Manuel,Perkams Lukas,Schmälzlein Marina,Graf Christopher,Fischer Jan-Patrick,Lechner Carolin,Hallstein Kerstin,Becker Stefan,Weyand Michael,Steegborn Clemens,Schultheiss Gerhard,Rose-John Stefan,Garbers Christoph,Unverzagt Carlo Angewandte Chemie (International ed. in English) A library of glycoforms of human interleukin 6 (IL-6) comprising complex and mannosidic N-glycans was generated by semisynthesis. The three segments were connected by sequential native chemical ligation followed by two-step refolding. The central glycopeptide segments were assembled by pseudoproline-assisted Lansbury aspartylation and subsequent enzymatic elongation of complex N-glycans. Nine IL-6 glycoforms were synthesized, seven of which were evaluated for in vivo plasma clearance in rats and compared to non-glycosylated recombinant IL-6 from E. coli. Each IL-6 glycoform was tested in three animals and reproducibly showed individual serum clearances depending on the structure of the N-glycan. The clearance rates were atypical, since the 2,6-sialylated glycoforms of IL-6 cleared faster than the corresponding asialo IL-6 with terminal galactoses. Compared to non-glycosylated IL-6 the plasma clearance of IL-6 glycoforms was delayed in the presence of larger and multibranched N-glycans in most cases. 10.1002/anie.202101496
    Therapeutic Interleukin-6 Trans-signaling Inhibition by Olamkicept (sgp130Fc) in Patients With Active Inflammatory Bowel Disease. Schreiber Stefan,Aden Konrad,Bernardes Joana P,Conrad Claudio,Tran Florian,Höper Hanna,Volk Valery,Mishra Neha,Blase Johanna Ira,Nikolaus Susanna,Bethge Johannes,Kühbacher Tanja,Röcken Christoph,Chen Minhu,Cottingham Ian,Petri Niclas,Rasmussen Birgitte B,Lokau Juliane,Lenk Lennart,Garbers Christoph,Feuerhake Friedrich,Rose-John Stefan,Waetzig Georg H,Rosenstiel Philip Gastroenterology BACKGROUND & AIMS:A large unmet therapeutic need exists in inflammatory bowel disease (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL6/IL6 receptor (IL6R) blockade is limited by profound immunosuppression. Evidence has emerged that chronic proinflammatory activity of IL6 is mainly mediated by trans-signaling via a complex of IL6 bound to soluble IL6R engaging the gp130 co-receptor without the need for membrane-bound IL6R. We have developed a decoy protein, sgp130Fc, that exclusively blocks IL6 proinflammatory trans-signaling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression. METHODS:We present a 12-week, open-label, prospective phase 2a trial (FUTURE) in 16 patients with active IBD treated with the trans-signaling inhibitor olamkicept (sgp130Fc) to assess the molecular mechanisms, safety, and effectiveness of IL6 trans-signaling blockade in vivo. We performed in-depth molecular profiling at various timepoints before and after therapy induction to identify the mechanism of action of olamkicept. RESULTS:Olamkicept was well tolerated and induced clinical response in 44% and clinical remission in 19% of patients. Clinical effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and marked transcriptional changes in the inflamed mucosa. An olamkicept-specific transcriptional signature, distinguishable from remission signatures of anti-tumor necrosis factor (infliximab) or anti-integrin (vedolizumab) therapies was identified. CONCLUSIONS:Our data suggest that blockade of IL6 trans-signaling holds great promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy for IBD. (EudraCT no., Nu 2016-000205-36). 10.1053/j.gastro.2021.02.062
    The role of interleukin-6 trans-signalling on cardiovascular dysfunction in inflammatory arthritis. Davies Ruth,Williams Jessica,Sime Katie,Jin Hyun-Sun,Thompson Charlotte,Jordan Lauren,Lang Derek,Halcox Julian P,Ellins Elizabeth,Jones Gareth W,Jones Simon A,Rose-John Stefan,Williams Anwen,Choy Ernest Rheumatology (Oxford, England) OBJECTIVES:Cardiovascular (CV) mortality in RA patients is 50% higher than in the general population. There is increasing recognition that systemic inflammation is a major driver of this. IL-6 is implicated in cardiovascular disease (CVD) in the general population but its role in CVD in RA is undefined. Of the two modes of IL-6 signalling, trans-signalling is pro-inflammatory whereas classical signalling is linked with inflammation resolution. This study examines the role of IL-6 trans-signalling in CVD in a mouse model and patients with RA. METHODS:Myography determined the effect of IL-6 trans-signalling blockade, using sgp130Fc, on aortic constriction in murine collagen-induced arthritis. Serum CCL2 and sVCAM-1 as soluble biomarkers of sIL-6R trans-signalling were investigated in a human cross-sectional study. An observational longitudinal study investigated the association between these biomarkers and progression of subclinical atherosclerosis in early RA by measuring carotid intima-media thickness (CIMT). RESULTS:sgp130Fc reduced arthritis severity, serum CCL2 and sVCAM-1 and restored vascular function in collagen-induced arthritis (CIA). In established RA, sVCAM-1 correlated with the 28-joint DAS (DAS28) and CV risk. In early RA, baseline DAS28 was associated with CIMT change at 6 months. CIMT 'rapid progressors' at 12 months had higher baseline sVCAM-1, haemoglobin A1c, cholesterol:high-density lipoprotein cholesterol ratio and LDL cholesterol. CONCLUSIONS:IL-6 trans-signalling plays a pivotal role in vascular dysfunction in CIA. In early RA, sVCAM-1 was associated with progression of subclinical atherosclerosis. Inflammation from RA onset in CVD-susceptible individuals may accelerate atherosclerosis. IL-6 trans-signalling blockade may be beneficial to RA patients and perhaps for atherosclerosis in the general population. 10.1093/rheumatology/keaa725
    Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland. Vennekens Annelies,Laporte Emma,Hermans Florian,Cox Benoit,Modave Elodie,Janiszewski Adrian,Nys Charlotte,Kobayashi Hiroto,Malengier-Devlies Bert,Chappell Joel,Matthys Patrick,Garcia Marie-Isabelle,Pasque Vincent,Lambrechts Diether,Vankelecom Hugo Proceedings of the National Academy of Sciences of the United States of America Stem cells in the adult pituitary are quiescent yet show acute activation upon tissue injury. The molecular mechanisms underlying this reaction are completely unknown. We applied single-cell transcriptomics to start unraveling the acute pituitary stem cell activation process as occurring upon targeted endocrine cell-ablation damage. This stem cell reaction was contrasted with the aging (middle-aged) pituitary, known to have lost damage-repair capacity. Stem cells in the aging pituitary show regressed proliferative activation upon injury and diminished in vitro organoid formation. Single-cell RNA sequencing uncovered interleukin-6 (IL-6) as being up-regulated upon damage, however only in young but not aging pituitary. Administering IL-6 to young mice promptly triggered pituitary stem cell proliferation, while blocking IL-6 or associated signaling pathways inhibited such reaction to damage. By contrast, IL-6 did not generate a pituitary stem cell activation response in aging mice, coinciding with elevated basal IL-6 levels and raised inflammatory state in the aging gland (inflammaging). Intriguingly, in vitro stem cell activation by IL-6 was discerned in organoid culture not only from young but also from aging pituitary, indicating that the aging gland's stem cells retain intrinsic activatability in vivo, likely impeded by the prevailing inflammatory tissue milieu. Importantly, IL-6 supplementation strongly enhanced the growth capability of pituitary stem cell organoids, thereby expanding their potential as an experimental model. Our study identifies IL-6 as a pituitary stem cell activator upon local damage, a competence quenched at aging, concomitant with raised IL-6/inflammatory levels in the older gland. These insights may open the way to interfering with pituitary aging. 10.1073/pnas.2100052118
    The novel cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP)-based mortality risk score in cardiogenic shock after acute myocardial infarction. Ceglarek Uta,Schellong Paul,Rosolowski Maciej,Scholz Markus,Willenberg Anja,Kratzsch Jürgen,Zeymer Uwe,Fuernau Georg,de Waha-Thiele Suzanne,Büttner Petra,Jobs Alexander,Freund Anne,Desch Steffen,Feistritzer Hans-Josef,Isermann Berend,Thiery Joachim,Pöss Janine,Thiele Holger European heart journal BACKGROUND:Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) still reaches excessively high mortality rates. This analysis is aimed to develop a new easily applicable biomarker-based risk score. METHODS AND RESULTS:A biomarker-based risk score for 30-day mortality was developed from 458 patients with CS complicating AMI included in the randomized CULPRIT-SHOCK trial. The selection of relevant predictors and the coefficient estimation for the prognostic model were performed by a penalized multivariate logistic regression analysis. Validation was performed internally, internally externally as well as externally in 163 patients with CS included in the randomized IABP-SHOCK II trial. Blood samples were obtained at randomization. The two trials are registered with ClinicalTrials.gov (NCT01927549 and NCT00491036), are closed to new participants, and follow-up is completed. Out of 58 candidate variables, the four strongest predictors for 30-day mortality were included in the CLIP score (cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide). The score was well calibrated and yielded high c-statistics of 0.82 [95% confidence interval (CI) 0.78-0.86] in internal validation, 0.82 (95% CI 0.75-0.89) in internal-external (temporal) validation, and 0.73 (95% CI 0.65-0.81) in external validation. Notably, it outperformed the Simplified Acute Physiology Score II and IABP-SHOCK II risk score in prognostication (0.83 vs 0.62; P < 0.001 and 0.83 vs. 0.76; P = 0.03, respectively). CONCLUSIONS:A biomarker-only score for 30-day mortality risk stratification in infarct-related CS was developed, extensively validated and calibrated in a prospective cohort of contemporary patients with CS after AMI. The CLIP score outperformed other clinical scores and may be useful as an early decision tool in CS. 10.1093/eurheartj/ehab110
    Interleukin-6 and Outcomes in Acute Heart Failure: An ASCEND-HF Substudy. Perez Antonio L,Grodin Justin L,Chaikijurajai Thanat,Wu Yuping,Hernandez Adrian F,Butler Javed,Metra Marco,Felker G Michael,Voors Adriaan A,McMurray John J,Armstrong Paul W,O'Connor Christopher,Starling Randall C,Tang W H Wilson Journal of cardiac failure BACKGROUND:The inflammatory cytokine IL-6 has been previously implicated in the pathophysiology of acute decompensated heart failure (HF). Prior observations in acute HF patients have suggested that IL-6 may be associated with outcomes and modulated by nesiritide. We aimed to evaluate the associations between serial IL-6 measurements, mortality and rehospitalization in acute HF. METHODS AND RESULTS:We analyzed the associations between IL-6 in acute HF, readmission, and mortality (30 and 180 days) using a cohort of 883 hospitalized patients from the ASCEND-HF trial (nesiritide vs placebo). Plasma IL-6 was measured at randomization (baseline), 48-72 hours, and 30 days. The median IL-6 was highest at baseline (14.1 pg/mL) and decreased at subsequent time points (7.6 pg/mL at 30 days). In a univariable Cox regression analysis, the baseline IL-6 was associated with 30- and 180-day mortality (hazard ratio per log 1.74, 95% confidence interval 1.09-2.78, P = .021; hazard ratio 3.23, confidence interval 1.18-8.86, P = .022, respectively). However, there was no association after multivariable adjustment. IL-6 at 48-72 hours was found to be independently associated with 30-day mortality (hazard ratio 8.2, confidence interval 1.2-57.5, P= .03), but not 180-day mortality in multivariable analysis that included the ASCEND-HF risk model and amino terminal pro-B-type natriuretic peptide as covariates. In comparison with placebo, nesiritide therapy was not associated with differences in serial IL-6 levels. CONCLUSIONS:Although elevated IL-6 levels were associated with higher all-cause mortality in acute HF, no independent association with this outcome was identified at baseline or 30-day measurements. In contrast with prior reports, we did not observe any impact of nesiritide over placebo on serial IL-6 levels. 10.1016/j.cardfail.2021.01.006
    Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Kang Sujin,Kishimoto Tadamitsu Experimental & molecular medicine Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman's disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19. 10.1038/s12276-021-00649-0
    Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases. Su Jian-Hui,Luo Meng-Yi,Liang Na-,Gong Shao-Xin,Chen Wei,Huang Wen-Qian,Tian Ying,Wang Ai-Ping Frontiers in pharmacology Cardio-Cerebrovascular Disease is a collective term for cardiovascular disease and cerebrovascular disease, being a serious threat to human health. A growing number of studies have proved that the content of inflammatory factors or mediators determines the stability of vascular plaque and the incidence of cardio-cerebrovascular event, and involves in the process of Cardio-Cerebrovascular Diseases. Interleukin-6 is a widely used cytokine that causes inflammation and oxidative stress, which would further result in cardiac and cerebral injury. The increased expression of interleukin-6 is closely related to atherosclerosis, myocardial infarction, heart failure and ischemic stroke. It is a key risk factor for these diseases by triggering inflammatory reaction and inducing other molecules release. Therefore, interleukin-6 may become a potential target for Cardio-Cerebrovascular Diseases in the future. This paper is aimed to discuss the expression changes and pathological mechanisms of interleukin-6 in Cardio-Cerebrovascular Diseases, and to provide a novel strategy for the prevention and treatment of Cardio-Cerebrovascular Diseases. 10.3389/fphar.2021.745061
    Interleukin-6 and intrapulmonary shunt. Perez-Vizcaino Francisco,Moreno Laura,Lorente José A The European respiratory journal 10.1183/13993003.01292-2021
    From RESCUE to ZEUS: will interleukin-6 inhibition with ziltivekimab prove effective for cardiovascular event reduction? Ridker Paul M Cardiovascular research 10.1093/cvr/cvab231
    The Tumor Necrosis Factor Alpha and Interleukin 6 Auto-paracrine Signaling Loop Controls Mycobacterium avium Infection via Induction of IRF1/IRG1 in Human Primary Macrophages. Gidon Alexandre,Louet Claire,Røst Lisa Marie,Bruheim Per,Flo Trude Helen mBio Macrophages sense and respond to pathogens by induction of antimicrobial and inflammatory programs to alert other immune cells and eliminate the infectious threat. We have previously identified the transcription factor IRF1 to be consistently activated in macrophages during Mycobacterium avium infection, but its precise role during infection is not clear. Here, we show that tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) autocrine/paracrine signaling contributes to controlling the intracellular growth of M. avium in human primary macrophages through activation of IRF1 nuclear translocation and expression of IRG1, a mitochondrial enzyme that produces the antimicrobial metabolite itaconate. Small interfering RNA (siRNA)-mediated knockdown of IRF1 or IRG1 increased the mycobacterial load, whereas exogenously provided itaconate was bacteriostatic at high concentrations. While the overall level of endogenous itaconate was low in M. avium-infected macrophages, the repositioning of mitochondria to M. avium phagosomes suggests a mechanism by which itaconate can be delivered directly to M. avium phagosomes in sufficient quantities to inhibit growth. Using mRNA hybridization, we further show that uninfected bystander cells actively contribute to the resolution of infection by producing IL-6 and TNF-α, which, via paracrine signaling, activate IRF1/IRG1 and strengthen the antimicrobial activity of infected macrophages. This mechanism contributes to the understanding of why patients on anti-inflammatory treatment, e.g., with tocilizumab or infliximab, can be more susceptible to mycobacterial disease. The prevalence of lung diseases caused by nontuberculous mycobacteria, such as Mycobacterium avium, is increasing in countries where tuberculosis is not endemic, most likely because of an aging population that is immunocompromised from underlying disease or immunosuppressive therapy. Our study contributes to the understanding of mycobacterial survival and killing in human macrophages and, more broadly, to the impact of immunometabolism during infection. We show evidence of an antimicrobial program in human primary macrophages where activation of the transcription factor IRF1 and expression of the mitochondrial enzyme IRG1 restrict the intracellular growth of M. avium, possibly by directed delivery of itaconate to M. avium phagosomes. The study also sheds light on why patients on immunosuppressive therapy are more susceptible to mycobacterial infections, since TNF-α and IL-6 contribute to driving the described antimycobacterial program. 10.1128/mBio.02121-21
    Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk. Clemens Melissa M,Kennon-McGill Stefanie,Vazquez Joel H,Stephens Owen W,Peterson Erich A,Johann Donald J,Allard Felicia D,Yee Eric U,McCullough Sandra S,James Laura P,Finck Brian N,McGill Mitchell R Acta pharmaceutica Sinica. B We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and -acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model. 10.1016/j.apsb.2021.08.024
    Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome. Batra Gorav,Ghukasyan Lakic Tatevik,Lindbäck Johan,Held Claes,White Harvey D,Stewart Ralph A H,Koenig Wolfgang,Cannon Christopher P,Budaj Andrzej,Hagström Emil,Siegbahn Agneta,Wallentin Lars, JAMA cardiology Importance:Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease. Objective:To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function. Design, Setting, and Participants:This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020. Exposures:Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2]). Main Outcomes and Measures:Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. Results:This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]). Conclusions and Relevance:In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment. 10.1001/jamacardio.2021.3079
    Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis. Journal of the American Heart Association Background Although trials suggest that anti-inflammatory approaches targeting interleukin (IL)-6 signaling can reduce cardiovascular risk, it remains unknown whether targeting IL-6 signaling could reduce risk additively to low-density lipoprotein cholesterol (LDL-C) lowering. Here, we assess interactions in associations of genetic downregulation of IL-6 signaling and LDL-C lowering with lifetime cardiovascular disease risk. Methods and Results Genetic scores for IL-6 signaling downregulation and LDL-C lowering were used to divide 408 225 White British individuals in UK Biobank into groups of lifelong exposure to downregulated IL-6 signaling, lower LDL-C, or both. Associations with risk of cardiovascular disease (coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, vascular death) were explored in factorial Mendelian randomization. Compared with individuals with genetic IL-6 and LDL-C scores above the median, individuals with LDL-C scores lower than the median but IL-6 scores above the median had an odds ratio (OR) of 0.96 (95% CI, 0.93-0.98) for cardiovascular disease. A similar OR (0.96; 95% CI, 0.93-0.98) was estimated for individuals with genetic IL-6 scores below the median but LDL-C scores above the median. Individuals with both genetic scores lower than the median were at lower odds of cardiovascular disease (OR, 0.92; 95% CI, 0.90-0.95). There was no interaction between the 2 scores (relative excess risk attributed to interaction index, 0; synergy index, 1; for multiplicative interaction=0.51). Genetic IL-6 score below the median was associated with lower cardiovascular disease risk across measured LDL-C strata (<100 or ≥100 mg/dL). Conclusions Genetically downregulated IL-6 signaling and genetically lowered LDL-C are associated with additively lower lifetime risk of cardiovascular disease. Future trials should explore combined IL-6 inhibition and LDL-C lowering treatments for cardiovascular prevention. 10.1161/JAHA.121.023277
    Paracrine Interleukin 6 Induces Cerebral Remodeling at Early Stages After Unilateral Common Carotid Artery Occlusion in Mice. Frontiers in cardiovascular medicine AIMS:Carotid artery disease is frequent and can result in chronic modest hypoperfusion of the brain. If no transient ischemic attack or stroke occur, it is classified asymptomatic. In the long-term, though, it can lead to cognitive impairment. Fostering cerebral remodeling after carotid artery occlusion might be a new concept of treatment. Paracrine Interleukin 6 (IL-6) can induce such remodeling processes at early stages. However, it has neurodegenerative long-term effects. With this exploratory study, we investigated the effect of paracrine IL-6 on cerebral remodeling in early stages after asymptomatic carotid artery occlusion to identify new treatment targets. METHODS AND RESULTS:To mimic a human asymptomatic carotid artery disease, we used a mouse model of unilateral common carotid artery (CCA) occlusion. We developed a mouse model for inducible paracrine cerebral IL-6 expression (Cx30-Cre-ERT2;FLEX-IL6) and induced IL-6 2 days after CCA occlusion. We studied the effects of paracrine IL-6 after CCA occlusion on neuronal connectivity using diffusion tensor imaging and on local proteome regulations of the hypo-perfused striatum and contralateral motor cortex using mass spectrometry of laser capture micro-dissected tissues. Paracrine IL-6 induced cerebral remodeling leading to increased inter-hemispheric connectivity and changes in motor system connectivity. We identified changes in local protein abundance which might have adverse effects on functional outcome such as upregulation of Synuclein gamma (Sncg) or downregulation of Proline Dehydrogenase 1 (Prodh). However, we also identified changes in local protein abundance having potentially beneficial effects such as upregulation of Caprin1 or downregulation of GABA transporter 1 (Gat1). CONCLUSIONS:Paracrine cerebral IL-6 at early stages induces changes in motor system connectivity and the proteome after asymptomatic CCA occlusion. Our results may help to distinguish unfavorable from beneficial IL-6 dependent protein regulations. Focusing on these targets might generate new treatments to improve long-term outcome in patients with carotid artery disease. 10.3389/fcvm.2021.805095
    Circulating Interleukin-6 Levels and Incident Ischemic Stroke: A Systematic Review and Meta-analysis of Prospective Studies. Neurology BACKGROUND AND OBJECTIVES:Human genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. However, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. We set out to perform a systematic review and meta-analysis of aggregate data on cohort studies to determine the magnitude and shape of the association between circulating IL-6 levels and risk of incident ischemic stroke in the general population. METHODS:Following the PRISMA guidelines, we systematically screened the PubMed search engine from inception to March 2021 for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effects models and explored nonlinear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS). We used funnel plots and trim-to-fill analyses to assess publication bias. RESULTS:We identified 11 studies (n = 27,411 individuals; 2,669 stroke events) meeting our eligibility criteria. Mean age of all included participants was 60.5 years and 54.8% were female. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7-9). In meta-analyses, 1 SD increment in circulating log-transformed IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (relative risk 1.19; 95% confidence interval 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias. DISCUSSION:Higher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke. 10.1212/WNL.0000000000013274
    Local and systemic effects of interleukin-6 (IL-6) in inflammation and cancer. FEBS letters Interleukin-6 (IL-6) is an inflammatory cytokine, the level of which is highly elevated in most, if not all, inflammatory states. IL-6 triggers cell type-specific responses and acts on target cells via a specific interleukin-6 receptor (IL-6R), which, together with IL-6, binds to and induces the dimerization of a second receptor subunit, gp130. IL-6 also binds to soluble IL-6R, and this complex interacts with gp130, regardless of IL-6R expression. This allows cells that do not express IL-6R and would be otherwise insensitive to IL-6 to respond to it. We have generated a constitutively active version of gp130 by forced leucine-zipper-mediated dimerization, named L-gp130. Once inserted into the Rosa26 locus of mice, L-gp130 can be activated in a cell-autonomous manner by crossing these mice with any Cre-recombinase transgenic mouse strain. Activation of gp130 in hepatocytes produced liver-specific effects such as the induction of acute-phase proteins, but it also had profound systemic effects on the immune system. Such local and systemic effects of interleukin-6 will be reviewed. 10.1002/1873-3468.14220
    Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. The European respiratory journal BACKGROUND:Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. METHODS:We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor () variant (rs7529229), known to associate with circulating IL-6R levels. RESULTS:We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead variant on risk of PAH (OR 0.99, p=0.88). CONCLUSION:Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect. 10.1183/13993003.02463-2020
    Up-regulation of MIAT aggravates the atherosclerotic damage in atherosclerosis mice through the activation of PI3K/Akt signaling pathway. Sun Guoqiang,Li Yubo,Ji Zhiyong Drug delivery This study is performed to elucidate the role of long non-coding RNA myocardial infarction associated transcript (lncRNA MIAT) in vulnerable plaque formation in rats with atherosclerosis (AS) through the regulation of the PI3K/Akt signaling pathway. The mice model of AS was established, and the successful modeled AS mice were treated with overexpressed MIAT and silenced MIAT. The levels of blood lipids, atherosclerotic plaques (AP) formation, the lipid content, collagen content, apoptosis of aortic cells, angiogenesis as well as the expression of inflammatory factors, such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were determined through a series of experiments. MIAT was found to be upregulated in AS. Additionally, MIAT up-regulated the levels of blood lipids, promoted AP formation, increased the lipid content and decreased the collagen content of AP, promoted the apoptosis of aortic cells in AS mice by activating the PI3K/Akt signaling pathway. Meanwhile, MIAT was determined to promote angiogenesis as well as the expression of inflammatory factors (IL-1β, IL-6, and TNF-α) in AS mice through the activation of the PI3K/Akt signaling pathway. Furthermore, MIAT activated the PI3K/Akt signaling pathway to participate in AS progression. Our study suggests that upregulation of MIAT can aggravate AS injury in AS mice via the activation of the PI3K/Akt signaling pathway, which could provide a novel target for the treatment of AS. 10.1080/10717544.2019.1628116
    Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis. Khatana Chainika,Saini Neeraj K,Chakrabarti Sasanka,Saini Vipin,Sharma Anil,Saini Reena V,Saini Adesh K Oxidative medicine and cellular longevity Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular events contributing to the most considerable number of morbidity and mortality worldwide. Factors like cellular senescence, genetics, clonal haematopoiesis, sedentary lifestyle-induced obesity, or diabetes mellitus upsurge the tendency of atherosclerosis and are foremost pioneers to definitive transience. Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed. Researchers tussle to demonstrate a clear understanding of treating mechanisms. A century of research suggests that lowering LDL, statin-mediated treatment, HDL, and lipid-profile management should be of prime interest to retard atherosclerosis-induced deaths. We shall brief the Ox-LDL-induced atherogenic mechanism and the treating measures in line to impede the development and progression of atherosclerosis. 10.1155/2020/5245308
    Development of a nomogram that predicts the risk for coronary atherosclerotic heart disease. Huang Shuna,Xie Xiaoxu,Sun Yi,Zhang Tingxing,Cai Yingying,Xu Xingyan,Li Huangyuan,Wu Siying Aging Studies seldom combine biological, behavioral and psychological factors to estimate coronary atherosclerotic heart disease (CHD) risk. Here, we evaluated the associations between these factors and CHD to develop a predictive nomogram to identify those at high risk of CHD. This case-control study included 4392 participants (1578 CHD cases and 2814 controls) in southeast China. Thirty-three biological, behavioral and psychological variables were evaluated. Following multivariate logistic regression analysis, which revealed eight risk factors associated with CHD, a predictive nomogram was developed based on a final model that included the three non-modifiable (sex, age and family history of CHD) and five modifiable (hypertension, hyperlipidemia, diabetes, recent experience of a major traumatic event, and anxiety) variables. The higher total nomogram score, the greater the CHD risk. Final model accuracy (as estimated from the area under the receiver operating characteristic curve) was 0.726 (95% confidence interval: 0.709-0.747). Validation analysis confirmed the high accuracy of the nomogram. High risk of CHD was associated with several biological, behavioral and psychological factors. We have thus developed an intuitive nomogram that could facilitate development of preliminary prevention strategies for CHD. 10.18632/aging.103216
    Corrigendum: Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T17 cells. Heink Sylvia,Yogev Nir,Garbers Christoph,Herwerth Marina,Aly Lilian,Gasperi Christiane,Husterer Veronika,Croxford Andrew L,Möller-Hackbarth Katja,Bartsch Harald S,Sotlar Karl,Krebs Stefan,Regen Tommy,Blum Helmut,Hemmer Bernhard,Misgeld Thomas,Wunderlich Thomas F,Hidalgo Juan,Oukka Mohamed,Rose-John Stefan,Schmidt-Supprian Marc,Waisman Ari,Korn Thomas Nature immunology 10.1038/ni0417-474b
    Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T17 cells. Heink Sylvia,Yogev Nir,Garbers Christoph,Herwerth Marina,Aly Lilian,Gasperi Christiane,Husterer Veronika,Croxford Andrew L,Möller-Hackbarth Katja,Bartsch Harald S,Sotlar Karl,Krebs Stefan,Regen Tommy,Blum Helmut,Hemmer Bernhard,Misgeld Thomas,Wunderlich Thomas F,Hidalgo Juan,Oukka Mohamed,Rose-John Stefan,Schmidt-Supprian Marc,Waisman Ari,Korn Thomas Nature immunology The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the T17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic T17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic T17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of T17-cell-mediated autoimmune diseases. 10.1038/ni.3632
    Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines. Murakami Masaaki,Kamimura Daisuke,Hirano Toshio Immunity Since the molecular cloning of interleukin-6 (IL-6) in 1986, many other cytokines have been found to share the same signal transducer, gp130, in their receptor complexes. Thus, the IL-6 family of cytokines now consists of ten members. Although some of the family members' functions are redundant as a result of the expression of gp130, there are also functional distinctions between members. The mechanisms that determine functional redundancies and distinctions are not completely understood. Yet, research has clarified the role of IL-6 family cytokines in autoimmune diseases and has led to effective therapies that target them. Here, we review the IL-6 family of cytokines in autoimmune diseases, with a particular focus on the prototypical member IL-6, from the viewpoints of their structure, signaling, and biological features and discuss possible mechanisms of their functional pleiotropy. 10.1016/j.immuni.2019.03.027
    Targeting Interleukin-6 Signaling in Clinic. Kang Sujin,Tanaka Toshio,Narazaki Masashi,Kishimoto Tadamitsu Immunity Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in immunity, tissue regeneration, and metabolism. Rapid production of IL-6 contributes to host defense during infection and tissue injury, but excessive synthesis of IL-6 and dysregulation of IL-6 receptor signaling is involved in disease pathology. Therapeutic agents targeting the IL-6 axis are effective in rheumatoid arthritis, and applications are being extended to other settings of acute and chronic inflammation. Recent studies reveal that selective blockade of different modes of IL-6 receptor signaling has different outcomes on disease pathology, suggesting novel strategies for therapeutic intervention. However, some inflammatory diseases do not seem to respond to IL-6 blockade. Here, we review the current state of IL-6-targeting approaches in the clinic and discuss how to apply the growing understanding of the immunobiology of IL-6 to clinical decisions. 10.1016/j.immuni.2019.03.026
    Historical overview of the interleukin-6 family cytokine. Kang Sujin,Narazaki Masashi,Metwally Hozaifa,Kishimoto Tadamitsu The Journal of experimental medicine Interleukin-6 (IL-6) has been identified as a 26-kD secreted protein that stimulates B cells to produce antibodies. Later, IL-6 was revealed to have various functions that overlap with other IL-6 family cytokines and use the common IL-6 signal transducer gp130. IL-6 stimulates cells through multiple pathways, using both membrane and soluble IL-6 receptors. As indicated by the expanding market for IL-6 inhibitors, it has become a primary therapeutic target among IL-6 family cytokines. Here, we revisit the discovery of IL-6; discuss insights regarding the roles of this family of cytokines; and highlight recent advances in our understanding of regulation of IL-6 expression. 10.1084/jem.20190347
    Interleukin-6: designing specific therapeutics for a complex cytokine. Garbers Christoph,Heink Sylvia,Korn Thomas,Rose-John Stefan Nature reviews. Drug discovery Interleukin-6 (IL-6) is a pivotal cytokine with a diverse repertoire of physiological functions that include regulation of immune cell proliferation and differentiation. Dysregulation of IL-6 signalling is associated with inflammatory and lymphoproliferative disorders such as rheumatoid arthritis and Castleman disease, and several classes of therapeutics have been developed that target components of the IL-6 signalling pathway. So far, monoclonal antibodies against IL-6 or IL-6 receptor (IL-6R) and Janus kinases (JAK) inhibitors have been successfully developed for the treatment of autoimmune diseases such as rheumatoid arthritis. However, clinical trials of agents targeting IL-6 signalling have also raised questions about the diseases and patient populations for which such agents have an appropriate benefit-risk profile. Knowledge from clinical trials and advances in our understanding of the complexities of IL-6 signalling, including the potential to target an IL-6 trans-signalling pathway, are now indicating novel opportunities for therapeutic intervention. In this Review, we overview the roles of IL-6 in health and disease and analyse progress with several approaches of inhibiting IL-6-signalling, with the aim of illuminating when and how to apply IL-6 blockade. 10.1038/nrd.2018.45
    The role of IL-6 in host defence against infections: immunobiology and clinical implications. Rose-John Stefan,Winthrop Kevin,Calabrese Leonard Nature reviews. Rheumatology IL-6 is a pleiotropic cytokine with broad-ranging effects within the integrated immune response. One of the roles of IL-6 is to support immunocompetence, defined as the ability of a host to respond to infections. Understanding the precise role of this cytokine in immunocompetence requires a critical appraisal of data derived from both preclinical and clinical studies. Primary immunodeficiency diseases involving IL-6 or its signalling pathways reveal that IL-6 is critical in the defence against numerous types of pathogens. Studies of IL-6 signalling in preclinical models reveal that selective inhibition of either classic IL-6 signalling or IL-6 trans-signalling has differential effects on the host response to different types of infections. Knowledge of such variation might inform bioengineering of new IL-6-targeting molecules and potentially enable modulation of their toxicity. Clinical studies of IL-6 inhibitors, mainly tocilizumab, reveal that their use is associated with an increased rate of both serious and opportunistic infections generally in the range observed with other non-IL-6 directed biologic therapies. Targeting IL-6 has several other important clinical implications related to diagnosis, management and prevention of infectious diseases. 10.1038/nrrheum.2017.83