Vascular endothelial growth factor-A as a promising therapeutic target for the management of psoriasis.
Luengas-Martinez Andrea,Hardman-Smart Jonathan,Paus Ralf,Young Helen S
Vascular endothelial growth factor-A (VEGF-A), the main angiogenic mediator, plays a critical role in the pathogenesis of several inflammatory immune-mediated diseases, including psoriasis. Even though anti-angiogenic therapies, such as VEGF inhibitors, are licensed for the treatment of various cancers and eye disease, VEGF-targeting interventions are not part of current psoriasis therapy. In this viewpoint essay, we argue that the existing preclinical research evidence on the role of VEGF-A in the pathogenesis of psoriasis as well as clinical observations in patients who have experienced psoriasis remission during oncological anti-VEGF-A therapy strongly suggests to systematically explore angiogenesis targeting also in the management of psoriasis. We also point out that some psoriasis therapies decrease circulating levels of VEGF-A and normalise the psoriasis-associated vascular pathology in the papillary dermis of plaques of psoriasis and that a subset of patients with constitutionally high levels of VEGF-A may benefit most from the anti-angiogenic therapy we advocate here. Given that novel, well-targeted personalised medicine therapies for the development of psoriasis need to be developed, we explore the hypothesis that VEGF-A and signalling through its receptors constitute a promising target for therapeutic intervention in the future management of psoriasis.
Counter-regulation of T cell effector function by differentially activated p38.
Alam Muhammad S,Gaida Matthias M,Ogawa Youichi,Kolios Antonios G A,Lasitschka Felix,Ashwell Jonathan D
The Journal of experimental medicine
Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway). Using mice expressing p38α and p38β with Y323F substitutions, we show that alternatively but not MAPK cascade-activated p38 up-regulates the transcription factors NFATc1 and IRF4, which are required for proliferation and cytokine production. Conversely, activation of p38 with UV or osmotic shock mitigated TCR-mediated activation by phosphorylation and cytoplasmic retention of NFATc1. Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323(+) T cell IRF4 and IL-17 production. Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.
The regulation of Th1 responses by the p38 MAPK.
Yang Ziyan,Zhang Xia,Darrah Patricia A,Mosser David M
Journal of immunology (Baltimore, Md. : 1950)
IL-12 is a dimeric cytokine that is produced primarily by APCs. In this study we examined the role that the p38 MAPKs (MAPK/p38) play in regulating IL-12 production. We show that inhibition of p38 dramatically increased IL-12 production upon stimulation, while decreasing TNF-α. This reciprocal effect on these two cytokines following MAPK/p38 inhibition occurred in many different APCs, following a variety of different stimuli. IL-12 production was also increased in macrophages treated with small interfering RNA to limit p38α expression, and in macrophages deficient in MKK3, a kinase upstream of p38. The increase in IL-12 production following MAPK/p38 inhibition appears to be due to enhanced IL-12 (p40) mRNA stability. We show that MAPK/p38 inhibition can promote Th1 immune responses and thereby enhance vaccine efficacy against leishmaniasis. In a mouse model of Leishmania major infection, vaccination with heat-killed L. major plus CpG and SB203580 elicited complete protection against infection compared with heat-killed L. major plus CpG without SB203580. Thus, this work suggests that MAPK/p38 inhibitors may be applied as adjuvants to bias immune responses and improve vaccinations against intracellular pathogens.
MicroRNA let-7b inhibits keratinocyte differentiation by targeting IL-6 mediated ERK signaling in psoriasis.
Wu Yan,Liu Liu,Bian Chunxiang,Diao Qingchun,Nisar Muhammad Farrukh,Jiang Xuemei,Bartsch Jörg W,Zhong Maojiao,Hu Xiangyu,Zhong Julia Li
Cell communication and signaling : CCS
BACKGROUND:The extensive involvement of microRNA (miRNA) in the pathophysiology of psoriasis is well documented. However, in order for this information to be useful in therapeutic manipulation of miRNA levels, it is essential that detailed functional mechanisms are elucidated. This study aimed to explore the effects of IL-6 targeting by let-7b and ERK1/2 mediated signaling on keratinocyte differentiation in psoriasis. METHODS:Following imiquimod cream (IMQ) application to let-7b (keratinocyte-specific let-7b overexpression mouse) and control mice for 7 days, we analyzed erythema, scaling and thickening of skin. A dual luciferase reporter assay and bioinformatics was carried out to detect target gene of let-7b. Additionally, the differentiation markers were measured. Immunohistochemistry analyses demonstrate a relationship of let-7b with IL-6 and ERK signaling. RESULTS:we found let-7b inhibits acanthosis and reduces the disease severity by treatment with IMQ compared to wild-type mice. Further study illustrated that let-7b promotes differentiation of keratinocytes in vivo and in vitro. Using bioinformatics and reporter gene assays, we found that IL-6 is a target gene of let-7b. In psoriasis, high expression levels of IL-6 lead to increased acivation of p-ERK1/2. High levels of let-7b transgene expression suppresses IL-6 expression and leads to increased keratinocyte differentiation. Moreover, let-7b acts as an upstream negative regulator of the ERK signaling pathway in keratinocytes of psoriasis. CONCLUSIONS:Our result reveals a previously unknown mechanism for regulation of IL-6 levels during psoriasis by let-7b and highlights a critical role for the ERK1/2 signaling pathway in epidermal differentiation during psoriasis. TRIAL REGISTRATION:The ethical approval for this study was from the Affiliated Hospital of Medical University of Anhui _ Fast_ PJ2017-11-14.
Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses.
Mercurio Laura,Failla Cristina M,Capriotti Lorena,Scarponi Claudia,Facchiano Francesco,Morelli Martina,Rossi Stefania,Pagnanelli Gianluca,Albanesi Cristina,Cavani Andrea,Madonna Stefania
In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36α, IL-36β and IL-36γ are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36γ. This cytokine was strongly induced by IL-17A and, together with IL-17A, efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors. Both IL-36γ and IL-17A induced cell proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 and NF-κB, respectively. We highlighted the intense IL-17A- and IL-36γ -dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. IL-17A or IL-36γ showed in HDMECs a synergic activity with TNF-α by potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36γ and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived IL-36γ represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but did not act on expression of adhesion molecules in HDMECs. On the other hand, inhibition of IL-36γ released by IL-17A-treated keratinocytes impaired either proliferation or ICAM-1 expression both in HDMECs and in an in vivo murine model of psoriasis. Taken together, our data demonstrated that IL-17A and IL-36γ are highly involved in endothelial cells/keratinocytes crosstalk in inflammatory skin conditions.
PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis.
Martini Silvia,Pozzi Giulia,Carubbi Cecilia,Masselli Elena,Galli Daniela,Di Nuzzo Sergio,Banchini Antonio,Gobbi Giuliana,Vitale Marco,Mirandola Prisco
European journal of immunology
PKCε is implicated in T cell activation and proliferation and is overexpressed in CD4 -T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune-mediated disorders is still largely unknown. We studied PKCε expression in circulating CD4 -T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4 subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCε is overexpressed in CD4 -T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCε interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCε is forcibly downregulated, CD4 -T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17-lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCε as a potential target in Th17-mediated diseases.
Immune Regulation of TNFAIP3 in Psoriasis through Its Association with Th1 and Th17 Cell Differentiation and p38 Activation.
Jiang Yanyun,Wang Wenming,Zheng Xiaofeng,Jin Hongzhong
Journal of immunology research
Background:Psoriasis is an immune-mediated chronic inflammatory skin disorder in which the dysregulation of immune cells plays an important role in its development. Tumor necrosis factor- (TNF-) antagonists affect the immune repertoire, while TNF--induced protein 3 (TNFAIP3) has a protective role against the deleterious effects of inflammation and participates in immune regulation. Objective:We investigated the immune regulation of in the pathogenesis of psoriasis and determined whether it is involved in the antipsoriatic effect of TNF- antagonists. Methods:mRNA levels were evaluated in blood from patients with moderate-to-severe psoriasis. The effects of TNF- antagonists were examined in a mouse imiquimod- (IMQ-) induced psoriasis-like dermatitis model. In the mouse model, mRNA expression was determined using RT-PCR. Serum levels of IL-17A, IL-23, IFN-, TNF-, phosphorylated ERK1/2, p38, and JNK were measured using ELISA. The proportion of Th1 and Th17 cells in mouse spleens was analyzed using flow cytometry. Results:mRNA expression levels of in the blood were significantly lower in patients with moderate and severe psoriasis (mean ± SD = 0.44 ± 0.25) compared with normal subjects (mean ± SD = 1.00 ± 0.82) ( < 0.01). In the mouse model, IMQ downregulated expression levels, which were increased after TNF- antagonist treatment ( < 0.05). Serum levels of Th17 cytokines (IL-17A and IL-23) and Th1 cytokines (IFN- and TNF-) were significantly higher in the IMQ and IMQ/rat IgG1 groups compared with the control group, and the application of TNF- antagonists significantly decreased the levels of inflammatory cytokines ( < 0.01). Notably, phosphorylated p38 levels were increased in the IMQ and IMQ/rat IgG1 groups compared with the control group but were downregulated by treatment with TNF- antagonists ( < 0.05). Th1 and Th17 cells were significantly increased in the IMQ group compared with the control group ( < 0.01). Conclusion: downregulation associated with Th1 and Th17 cell differentiation and p38 activation might contribute in part to the mechanism of immune dysfunction in psoriasis. TNF- antagonists might partly exert their effects on psoriasis via this pathway.
The role of Th17 cells in psoriasis.
Li Binbin,Huang Liangliang,Lv Peng,Li Xiang,Liu Ge,Chen Yan,Wang Ziyu,Qian Xiaoxian,Shen Yixiao,Li Yunman,Fang Weirong
T helper 17 (Th17) cells have been involved in the pathogenesis of many autoimmune and inflammatory diseases, like psoriasis, multiple sclerosis (MS), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). However, the role of Th17 cells in psoriasis has not been clarified completely. Th17-derived proinflammatory cytokines including IL-17A, IL-17F, IL-21, IL-22, and IL-26 have a critical role in the pathogenesis of these disorders. In this review, we introduced the signaling and transcriptional regulation of Th17 cells. And then, we demonstrate the immunopathology role of Th17 cells and functions of the related cytokines in the psoriasis to get a better understanding of the inflammatory mechanisms mediated by Th17 cells in this disease.
Hypertonic saline downregulates endothelial cell-derived VEGF expression and reduces blood-brain barrier permeability induced by cerebral ischaemia via the VEGFR2/eNOS pathway.
Wang Qiaosheng,Deng Yiyu,Huang Linqiang,Zeng Wenxin,Chen Shenglong,Lv Bo,Jiang Wenqiang,Han Yongli,Ding Hongguang,Wen Miaoyun,Zeng Hongke
International journal of molecular medicine
The aim of the present study was to explore the possible mechanisms by which hypertonic saline (HS) effectively ameliorates cerebral oedema via the vascular endothelial growth factor receptor 2 (VEGFR2)‑mediated endothelial nitric oxide synthase (eNOS) pathway of endothelial cells in rats. A middle cerebral artery occlusion (MCAO) model in Sprague‑Dawley rats and an oxygen‑glucose deprivation (OGD) model in cells were used in the present study. Evans blue (EB) staining and a horseradish peroxidase flux assay were performed to evaluate the protective effect of 10% HS on the blood‑brain barrier (BBB). The expression levels of vascular endothelial growth factor (VEGF), VEGFR2, zonula occludens 1 (ZO1) and occludin were quantified. The results demonstrated that 10% HS effectively reduced EB extravasation in the peri‑ischaemic brain tissue. At 24 h after MCAO, the protein expression levels of VEGF and VEGFR2 in the peri‑ischaemic brain tissue were downregulated following treatment with 10% HS. In vitro experiments demonstrated that the permeability of a monolayer endothelial cell barrier was decreased significantly following HS treatment. In addition, VEGF and VEGFR2 protein expression levels were increased in endothelial cells under hypoxic conditions, but that effect was suppressed by HS treatment. Furthermore, HS inhibited the downregulation of ZO1 and occludin effectively, possibly through the VEGFR2/phospholipase C γ1 (PLCγ1)/eNOS signalling pathway. In conclusion, 10% HS may alleviate cerebral oedema through reducing ischaemia‑induced BBB permeability, as a consequence of inhibiting VEGFR2/PLCγ1/eNOS‑mediated downregulation of ZO1 and occludin.
Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia.
Kunstfeld Rainer,Hirakawa Satoshi,Hong Young-Kwon,Schacht Vivien,Lange-Asschenfeldt Bernhard,Velasco Paula,Lin Charles,Fiebiger Edda,Wei Xunbin,Wu Yan,Hicklin Daniel,Bohlen Peter,Detmar Michael
Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4+ T-lymphocytes and epidermal CD8+ lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy.
Mechanistic insight into activation of MAPK signaling by pro-angiogenic factors.
Song Min,Finley Stacey D
BMC systems biology
BACKGROUND:Angiogenesis is important in physiological and pathological conditions, as blood vessels provide nutrients and oxygen needed for tissue growth and survival. Therefore, targeting angiogenesis is a prominent strategy in both tissue engineering and cancer treatment. However, not all of the approaches to promote or inhibit angiogenesis lead to successful outcomes. Angiogenesis-based therapies primarily target pro-angiogenic factors such as vascular endothelial growth factor-A (VEGF) or fibroblast growth factor (FGF) in isolation. However, pre-clinical and clinical evidence shows these therapies often have limited effects. To improve therapeutic strategies, including targeting FGF and VEGF in combination, we need a quantitative understanding of the how the promoters combine to stimulate angiogenesis. RESULTS:In this study, we trained and validated a detailed mathematical model to quantitatively characterize the crosstalk of FGF and VEGF intracellular signaling. This signaling is initiated by FGF binding to the FGF receptor 1 (FGFR1) and heparan sulfate glycosaminoglycans (HSGAGs) or VEGF binding to VEGF receptor 2 (VEGFR2) to promote downstream signaling. The model focuses on FGF- and VEGF-induced mitogen-activated protein kinase (MAPK) signaling and phosphorylation of extracellular regulated kinase (ERK), which promotes cell proliferation. We apply the model to predict the dynamics of phosphorylated ERK (pERK) in response to the stimulation by FGF and VEGF individually and in combination. The model predicts that FGF and VEGF have differential effects on pERK. Additionally, since VEGFR2 upregulation has been observed in pathological conditions, we apply the model to investigate the effects of VEGFR2 density and trafficking parameters. The model predictions show that these parameters significantly influence the response to VEGF stimulation. CONCLUSIONS:The model agrees with experimental data and is a framework to synthesize and quantitatively explain experimental studies. Ultimately, the model provides mechanistic insight into FGF and VEGF interactions needed to identify potential targets for pro- or anti-angiogenic therapies.
Effect of RNA Interference Targeting Gene Combined with Ultrasonic Irradiation and SonoVue Microbubbles on Proliferation and Apoptosis in Keratinocytes of Psoriatic Lesions.
Ran Li-Wei,Wang Hao,Lan Dong,Jia Hong-Xia,Yu Si-Si
Chinese medical journal
Background:Signal transducer and activator of transcription 3 (STAT3) was strongly expressed and activated in psoriatic keratinocytes (KCs) and correlated with the severity of psoriasis. The study aimed to investigate the effects of STAT3 small interfering RNA (siRNA) combined with ultrasonic irradiation and SonoVue microbubbles on the proliferation and apoptosis in KCs of psoriatic lesions and the relative mechanisms. Methods:Psoriatic KCs were transfected under four experimental conditions: (1) STAT3 siRNA carried by Lipofectamine 3000 combined with ultrasonic irradiation and SonoVue microbubbles (LUS group); (2) STAT3 siRNA only carried by Lipofectamine 3000 (L group); (3) the negative control of siRNA carried by Lipofectamine 3000 combined with ultrasonic irradiation and SonoVue microbubbles (siRNA-NC); (4) not treated as Blank. Cell Counting Kit-8 assay was used to evaluate the cell proliferation. Cell cycle analysis was detected with cycle test Plus DNA reagent kit associated with flow cytometer. FITC Annexin V apoptosis detection kit associated with flow cytometer was applied for apoptosis analysis. Fluo calcium indicator associated with flow cytometer was used to analyze intracellular free calcium concentration ([Ca]). The expressions of cyclin D1 and Bcl-xL were detected both at the mRNA level by real-time reverse transcription-polymerase chain reaction (RT-PCR) and at the protein level by Western blotting. The obtained data were statistically evaluated by two-way analysis of variance. Results:STAT3 siRNA inhibited the growth of KCs in a time-dependent manner showing the highest proliferation inhibition in LUS group with proliferation ratio of 45.38% ± 5.85% at 72h (P < 0.05 vs. L group, siRNA-NC, or Blank). STAT3 siRNA induced an altered cell cycle distribution of KCs showing the highest increases in G2/M-phase population up to 18.06% ± 0.36% in LUS group (P < 0.05 vs. L group, siRNA-NC, or Blank). STAT3 siRNA induced late apoptosis of KCs with the highest late apoptosis percentage of 22.87% ± 1.28% in LUS group (P < 0.05 vs. L group, siRNA-NC, or Blank). STAT3 siRNA induced the elevation of [Ca]of KCs with the highest calcium fluorescence intensity mean of 1213.67 ± 60.51 in LUS group (P < 0.05 vs. L group, siRNA-NC, or Blank). STAT3 siRNA induced the downregulation of cyclin D1 and Bcl-xL expressions of KCs at mRNA and protein levels with the lowest expressions in LUS group with cyclin D1 expression of 51.81% ± 9.58% and 70.17% ± 4.22% at mRNA level and at protein level, respectively, and with Bcl-xL expression of 37.58% ± 4.92% and 64.06% ± 7.78% at mRNA level and at protein level, respectively (P < 0.05 vs. L group, siRNA-NC, or Blank). Conclusions:STAT3 siRNA inhibited the growth and induced the apoptosis in psoriatic KCs likely partly through altering cell cycle distribution, elevating [Ca], and downregulating cyclin D1 and Bcl-xL expressions. Silencing the target gene STAT3 in psoriatic KCs with siRNA combined with ultrasonic irradiation and microbubbles would contribute to a significant innovation as a new clinical therapy for psoriasis.
Multi-glycoside of Tripterygium wilfordii Hook. f. ameliorates imiquimod-induced skin lesions through a STAT3-dependent mechanism involving the inhibition of Th17-mediated inflammatory responses.
Zhao Jingxia,Di Tingting,Wang Yan,Liu Xin,Liang Daiying,Zhang Guangzhong,Li Ping
International journal of molecular medicine
Multi-glycoside of Tripterygium wilfordii Hook. f.(GTW) possesses anti-inflammatory and immunosuppressive properties, and has been used as a traditional treatment for psoriasis for many years, although the underlying immunological mechanisms remain poorly understood. The T helper (Th)17 cell response is considered to play a major role in the pathogenesis of psoriasis. Th17 cells are implicated in the mechanism of pathogenesis of imiquimod (IMQ)‑induced skin inflammation. Using a mouse model, we demonstrated that GTW protected mice from developing psoriasis-like lesions induced by topical IMQ administration. This protection was associated with significantly decreased mRNA levels of Th17 cytokines such as interleukin (IL)-17A, IL-17F and IL-22 in mouse skin samples as well as fewer IL-17-secreting splenic CD4+ lymphocytes in IMQ-exposed mice. There were no significant effects on the proportion of CD4+ interferon (IFN)-γ+ T cells, CD4+IL-4+ T cells and CD4+CD25+Foxp3+ Treg cells in the spleen cells. Taken together with the unchanged mRNA levels of Th1 cytokine IFN-γ, Th2 cytokine IL-4 and Treg cytokine IL-10 in IMQ-exposed mouse skin following GTW administration, our findings suggest that the immunosuppressive effect of GTW in psoriasis is exerted mainly on Th17 cells, rather than on Th1, Th2 or Treg cells. Furthermore, we showed that GTW suppressed Th17 function through the inhibition of STAT3 phosphorylation. These results have the potential to pave the way for the use of GTW as an agent for the treatment of psoriasis.
Cryptotanshinone reduces psoriatic epidermal hyperplasia via inhibiting the activation of STAT3.
Tang Lipeng,He Songmin,Wang Xieqi,Liu Hongying,Zhu Ying,Feng Bing,Su Zuqing,Zhu Wei,Liu Bo,Xu Fangfang,Li Chutian,Zhao Jie,Zheng Xirun,Lu Chuanjian,Zheng Guangjuan
The discovery of new therapeutic drugs with the efficacious and safe ability to prevent epidermal hyperplasia is extremely urgent for psoriasis. Cryptotanshinone (CTS), an active component isolated from the root of Salvia miltiorrhiza Bunge, has been reported to have antibacterial and antitumor effects. However, its effects on psoriasis have not been reported. Here, we investigated the therapeutic effects of CTS on imiquimod (IMQ)-induced psoriatic-like skin model and explored the underlying mechanisms. Our results revealed that CTS effectively alleviates IMQ-induced epidermal hyperplasia. In vitro studies also indicated that CTS potently inhibits the growth of keratinocytes. We further found that STAT3, a transcription factor for the cell growth, is the key mediator of CTS on the proliferation of keratinocytes. Taken together, our findings indicated that the curative effects of CTS on psoriasis are accomplished mainly through modulating STAT3, which providing evidences to develop CTS as a potential therapeutic agent for patients with psoriasis.
Withanolides, Extracted from Datura Metel L. Inhibit Keratinocyte Proliferation and Imiquimod-Induced Psoriasis-Like Dermatitis via the STAT3/P38/ERK1/2 Pathway.
Li Tingting,Wei Zheng,Sun Yanping,Wang Qiuhong,Kuang Haixue
Molecules (Basel, Switzerland)
Psoriasis is an immune-mediated inflammatory dermatosis characterized by epidermal hyperplasia and excessive infiltration of inflammatory cells. Withanolides, extracted from L.; are the main effective components for the treatment of psoriasis. However, the precise mechanisms of action of withanolides for the treatment of psoriasis remain unclear. We found that treatment with withanolides alleviated imiquimod (IMQ)-induced epidermal hyperplasia and inflammatory cell infiltration in the effective skin of model mice. In addition, we also found that withanolides suppressed the activation of STAT3, ERK1/2 and P38 signaling pathways in IMQ-stimulated HaCat cells. These results suggest that withanolides possess an anti-inflammatory effect and have significant therapeutic potential for the prevention and treatment of psoriasis.
Epidermal hyperplasia induced by Raf-MAPK signaling requires Stat3 activation.
Tarutani Masahito,Nakajima Kimiko,Takaishi Mikiro,Ohko Kentaro,Sano Shigetoshi
Journal of dermatological science
BACKGROUND:Raf is one of the downstream effectors of Ras GTPases, and plays a key role in regulating cell proliferation and differentiation through the activation of MAPK. We have previously demonstrated that temporal induction of Raf in the epidermis of K14-Raf:ER transgenic mice results in epidermal hyperplasia resembling squamous cell carcinoma and psoriasis. It has been demonstrated that epidermal Stat3 activation is required for psoriasis development, since keratinocyte-specific Stat3 activation in a mouse model elicits a psoriasis-like phenotype, which is reversed by inhibition of Stat3 signaling. OBJECTIVE:The aim of this study was whether Stat3 signaling is involved in Raf-MAPK-dependent epidermal hyperplasia. METHODS:K14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor ligand binding domain-Raf fusion gene is expressed under control of the keratin 14 promoter, were mated with epidermis-specific Stat3 null mice (K5-Cre.Stat3(flox/flox)). K5-Cre.Stat3(flox/flox) mice were used to define the impact of Stat3 deficiency on Raf-induced epidermal hyperplasia. RESULTS:Over-expression of Raf by 4OHT treatment in K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice greatly attenuated the epidermal hyperplasia and dermal cell infiltrates compared with K14-Raf:ER;K5-Cre.Stat3(flox/WT) mice. Also, up-regulation of psoriasis-associated cytokine profiles, including VEGF, was inhibited in the skin from K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice following 4OHT treatment. CONCLUSION:These results clearly indicate that Raf-MAPK-dependent psoriatic-like epidermal hyperplasia requires Stat3 signaling in keratinocytes.
ERK inhibitor JSI287 alleviates imiquimod-induced mice skin lesions by ERK/IL-17 signaling pathway.
Huang Xiaoling,Yu Pengxia,Liu Minyu,Deng Yifang,Dong Yuqiong,Liu Quanhai,Zhang Jintao,Wu Tong
Many studies confirmed that the over-activation of RAF-MEK-ERK signaling pathway plays a central role in human cancers. To avoid drug resistance during cancer treatment, many researchers focused on the study of the downstream therapeutic target of RAF-MEK-ERK signaling pathway. Therefore, ERK1/2 became a hot anticancer target. It has been shown that ERK phosphorylation could activate Th17 cells and therefore induce inflammatory diseases. Due to these results, inhibition of ERK, as a potential drug target, could provide a solution for autoimmune diseases, especially T cell mediated diseases. In this study, a small synthetic molecule JSI287 was found with the function of alleviating IMQ-induced mice skin lesions through ERK/IL-17 signaling pathway during the screening of small molecule databases targeting ERK. The results showed that JS1287 small molecule alleviated epidermal thickness, epidermis congestion, edema and inflammatory cell infiltration, decreased release of inflammatory cytokines of IL-6, IL-12 and IL-17A, and further regulated the mRNA expression of ATF1 and protein expression of ERK1/2 in IMQ-induced skin lesions. Our study suggested that ERK inhibitor JSI287 could be a promising candidate for psoriasis treatment.
Anti-psoriatic effects of Honokiol through the inhibition of NF-κB and VEGFR-2 in animal model of K14-VEGF transgenic mouse.
Wen Jiaolin,Wang Xianhuo,Pei Heying,Xie Caifeng,Qiu Neng,Li Shucai,Wang Wenwen,Cheng Xia,Chen Lijuan
Journal of pharmacological sciences
Honokiol (HK), a biphenolic neolignan isolated from Magnolia officinalis, has been reported to possess anti-inflammatory and anti-angiogenic activaties. In this study, our aim was to investigate anti-psoriatic activities of HK and the involved mechanisms. In vitro, the effects of HK on the regulation of Th1/Th2 and TNF-α-induced NF-κB (p65) activation were analyzed by respective FCS and immunofluorescence. Additionally, the K14-VEGF transgenic model was used for the in vivo study. ELISA and Q-PCR were performed to evaluate serum levels of Th1/Th2 cytokines and their corresponding mRNA expressions. Effects on VEGFR-2 and p65 activation, as well as other angiogenic and inflammatory parameters were studied by immunostainings. Importantly, we found that HK significantly decreased the ratio of Th1/Th2-expression CD4(+) T cells and inhibited TNF-α-induced activation of NF-κB. The morphology and histological features of psoriasis were effectively improved by HK treatment. The expression of TNF-α and IFN-γ, and their corresponding mRNA levels were down-regulated and the expression of nuclear p65, VEGFR-2, as well as related phosphorylated proteins (p-VEGFR-2, p-ERK1/2, p-AKT and p-p38) were also suppressed. Overall, these results in our study suggested that HK exhibits anti-psoriatic effects through the inhibition of NF-κB and VEGFR-2.
Topical Sunitinib ointment alleviates Psoriasis-like inflammation by inhibiting the proliferation and apoptosis of keratinocytes.
Kuang Ye-Hong,Lu Yan,Liu Ying-Ke,Liao Li-Qiu,Zhou Xing-Chen,Qin Qun-Shi,Jia Xue-Kun,Wu Li-Sha,Zhu Wu,Chen Xiang
European journal of pharmacology
Psoriasis is a chronic auto-immune inflammation disease with skin lesions and abnormal keratinocyte proliferation. Sunitinib, a multi-targeted tyrosine kinase inhibitor, is known to selectively inhibit several growth factor receptors, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and stem cell factor. It was reported that a patient with renal cell carcinoma (RCC) whose psoriatic lesion was resolved dramatically during treatment with Sunitinib, however, the mechanism is still unclear. We applied Sunitinib ointment to treat imiquimod-induced mouse model of psoriasis and found that Sunitinib ointment could alleviate imiquimod-induced psoriasis-like inflammation and reduce the Ki67 expression, while Sunitinib ointment couldn't reduce imiquimod-induced splenomegaly of the mouse model, then we concentrated on studying the effect of Sunitinib on the proliferation and apoptosis of keratinocytes, we cultivated HaCaT cells with epidermal growth factor (HaCaT/E cells) to represent as a state of highly proliferative psoriatic keratinocytes. We found that Sunitinib could inhibit the proliferation of Hacat/E cell in a time and concentration dependent manner by influencing the expression level of cell cycle protein D1, cycle protein E1, in addition, Sunitinib could induce the apoptosis of Hacat/E cell and up-regulate the expression of poly ADP-ribose polymerase (PARP). Sunitinib down-regulated the expression of phosphorylated signal transduction and activator of transcription 3 (p-Stat3) of Hacat/E cells significantly. We conclude that Sunitinib alleviates imiquimod-induced psoriasis-like inflammation by regulating the proliferation and apoptosis of HaCaT cells through inhibiting the expression of p-Stat3.
Phospholipase Cδ1 regulates p38 MAPK activity and skin barrier integrity.
Kanemaru Kaori,Nakamura Yoshikazu,Totoki Kengo,Fukuyama Takatsugu,Shoji Madoka,Kaneko Hisae,Shiratori Kanako,Yoneda Atsuko,Inoue Takafumi,Iwakura Yoichiro,Kabashima Kenji,Fukami Kiyoko
Cell death and differentiation
Keratinocytes undergo a unique type of programmed cell death known as cornification, which leads to the formation of the stratum corneum (SC), the main physical barrier of the epidermis. A defective epidermal barrier is a hallmark of the two most common inflammatory skin disorders, psoriasis, and atopic dermatitis. However, the detailed molecular mechanisms of skin barrier formation are not yet fully understood. Here, we showed that downregulation of phospholipase C (PLC) δ1, a Ca-mobilizing and phosphoinositide-metabolizing enzyme abundantly expressed in the epidermis, impairs the barrier functions of the SC. PLCδ1 downregulation also impairs localization of tight junction proteins. Loss of PLCδ1 leads to a decrease in intracellular Ca concentrations and nuclear factor of activated T cells activity, along with hyperactivation of p38 mitogen-activated protein kinase (MAPK) and inactivation of RhoA. Treatment with a p38 MAPK inhibitor reverses the barrier defects caused by PLCδ1 downregulation. Interestingly, this treatment also attenuates psoriasis-like skin inflammation in imiquimod-treated mice. These findings demonstrate that PLCδ1 is essential for epidermal barrier integrity. This study also suggests a possible link between PLCδ1 downregulation, p38 MAPK hyperactivation, and barrier defects in psoriasis-like skin inflammation.
Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis.
Sakurai Kenji,Dainichi Teruki,Garcet Sandra,Tsuchiya Soken,Yamamoto Yosuke,Kitoh Akihiko,Honda Tetsuya,Nomura Takashi,Egawa Gyohei,Otsuka Atsushi,Nakajima Saeko,Matsumoto Reiko,Nakano Yuri,Otsuka Masayuki,Iwakura Yoichiro,Grinberg-Bleyer Yenkel,Ghosh Sankar,Sugimoto Yukihiko,Guttman-Yassky Emma,Krueger James G,Kabashima Kenji
The Journal of allergy and clinical immunology
BACKGROUND:Psoriasis is a chronic inflammatory skin disease characterized by IL-17-mediated immune responses. p38 is known to be highly activated in the psoriatic epidermis; however, whether p38 is involved in the development of psoriasis is unclear. OBJECTIVE:We sought to demonstrate that activation of p38 mitogen-activated protein kinase is sufficient to induce psoriatic inflammation in mice and that cutaneous p38 activities are the topical therapeutic targets for psoriasis. METHODS:A p38 activator, anisomycin, was applied daily to murine skin. Transcriptomic analyses were performed to evaluate the similarities of the skin responses to those in human psoriasis and the existing animal model. BIRB796, a small-molecule inhibitor targeting p38 activities, was applied to the murine psoriatic models topically or to human psoriatic skin specimens ex vivo. RESULTS:Topical treatment with anisomycin induced key signatures in psoriasis, such as epidermal thickening, neutrophil infiltration, and gene expression of Il1a, Il1b, Il6, Il24, Cxcl1, Il23a, and Il17a, in treated murine skin. These responses were fully abrogated by topical treatment with BIRB796, and were reduced in IL-17A-deficient mice. Transcriptomic analyses demonstrated the similarities of anisomycin-induced dermatitis to human psoriasis and imiquimod-induced murine psoriatic dermatitis. Furthermore, BIRB796 targeting of p38 activities reduced expression of psoriasis-related genes in both human keratinocytes stimulated with recombinant IL-17A in vitro and psoriatic skin specimens ex vivo. CONCLUSION:Therefore our findings suggest that cutaneous p38 activation can be a key event in patients with psoriasis and a potential topical therapeutic target of a small molecule.
STAT3 but not STAT4 is critical for γδT17 cell responses and skin inflammation.
Agerholm Rasmus,Rizk John,Viñals Mònica Torrellas,Bekiaris Vasileios
The transcription factors STAT3 and STAT4 are essential for lymphocyte differentiation and function. Interleukin (IL)-17 producing γδ T (γδT17) cells are innate lymphocytes important for anti-bacterial and inflammatory responses at barrier surfaces. Herein, we examine the role of STAT3 and STAT4 in regulating the homeostasis, activation, and pathogenicity of γδT17 cells. We show that STAT3 sustains γδT17 numbers in the skin but not in the lymph nodes, while STAT4 deficiency does not affect their homeostasis. Similarly, STAT3 but not STAT4 is essential for IL-23-induced IL-22 production by γδT17 cells. Concomitantly, mice lacking STAT3 expression in γδT17 cells develop significantly reduced psoriasis-like inflammation. STAT3-deficient γδT17 cells fail to expand and to upregulate IL-17A, IL-17F, and IL-22 in response to psoriatic stimuli. Although STAT4-deficient animals develop psoriasis-like disease, γδT17 cells in these mice are defective in IL-17F production. Collectively, our data demonstrate for the first time a critical role for STAT3 in orchestrating the homeostasis and pathogenicity of γδT17 cells and provide evidence for the requirement of STAT4 for optimal cytokine responses during inflammation.
Impaired function of regulatory T cells in patients with psoriasis is mediated by phosphorylation of STAT3.
Yang Luting,Li Bing,Dang Erle,Jin Liang,Fan Xueli,Wang Gang
Journal of dermatological science
BACKGROUND:Psoriasis is a T cell-mediated chronic inflammatory skin disease. Regulatory T cells (Tregs) are crucial in suppressing immune response to maintain the immune balance. Wheras Tregs from psoriatic patients showed poorly activity in suppressing activation of responder T cells (Tresp), the mechanisms involved in this process are still unknown. OBJECTIVES:In this study, we investigated the possible role of STAT3 pathway in the pathogenesis of dysfunctional Tregs in psoriasis. METHODS:The suppressive function and the proliferative activity of Tregs were detected from psoriatic patients and normal healthy controls. Expression of phospho-STAT3 in psoriatic Tregs was evaluated by flow cytometry and immunofluorescence. Furthermore, Tregs were treated with Stattic V (STAT3 inhibitor) in order to investigate the role of STAT3 pathway in the function of Tregs. In addition, IL-6, IL-21 and IL-23 treatments were performed to identify the upstream molecules of STAT3 pathway in Tregs. RESULTS:Tregs from peripheral blood of psoriatic patients showed decreased suppressive function, together with phosphorylation of STAT3. In addition, Tregs isolated from psoriatic patients could produce IFN-γ, TNF-α and IL-17. In the co-culture system of Tregs and Tresp isolated from psoriatic patients, addition of STAT3 inhibitor partially restored the suppressive function of Tregs and restrained the expressions of IFN-γ, TNF-α and IL-17 in psoriatic patients. Moreover, we found that IL-6, IL-21 and IL-23 induced the phosphorylation of STAT3 in Tregs. CONCLUSIONS:Our findings suggest that psoriatic Tregs experience a predominant STAT3 phosphorylation by exposure to pro-inflammatory cytokines, leading to their impaired functions in suppressing Tresp activation.
Imiquimod Increases Cutaneous VEGF Expression in Imiquimod-induced Psoriatic Mouse Model.
Wu Hui-Hui,Xie Wen-Lin,Zhao Yu-Kun,Liu Juan-Hua,Luo Di-Qing
Current vascular pharmacology
Psoriasis is a chronic skin disease of unknown aetiology but increasing evidence suggests that cutaneous angiogenesis plays an important role. Vascular endothelial growth factor (VEGF) is one of the pro-angiogenic cytokines which is related to the pathogenesis of psoriasis. Our study evaluated the influence of imiquimod (IMQ) on VEGF in IMQ-induced mouse model. Balb/c female mice (n=16) 8-12 weeks of age were randomly divided into an experimental group (5% IMQ cream) and the control group (Vaseline cream). Serum levels of circulating VEGF-A were quantified by enzyme-linked immunosorbent assay. VEGF protein expression in tested skin was measured by western blotting and immunohistochemical staining. The tested skin in the experimental group expressed higher levels of VEGF protein than in the control group (p=0.012); immunohistochemical staining revealed that the cells over-expressing VEGF localized predominantly in the epidermis and vascular endothelium. Circulating VEGF-A levels showed no significant difference between the experimental and control groups (p=0.445). The IMQ-induced mouse psoriatic model showed an upregulation of VEGF in the skin lesions mimicking human psoriasis but the circulating VEGF-A levels showed no difference. This model may be useful to investigate the role of angiogenesis in psoriasis.
Targeting VEGF/VEGFR in the treatment of psoriasis.
Li Wei,Man Xiao-Yong,Chen Jia-Qi,Zhou Jiong,Cai Sui-Qing,Zheng Min
Psoriasis is a common chronic skin disorder characterized by cutaneous inflammation and keratinocyte hyperproliferation. In the past decade, a number of novel effective biological agents have been developed to treat moderate-to-severe psoriasis. However, these drugs have potential serious side effects, particularly the development of infectious diseases. Therefore there is still a need for new therapies with better efficacy and less adverse effects. Angiogenesis is implicated in various pathological conditions including psoriasis. Direct targeting of angiogenesis becomes a new therapeutic strategy for the treatment of psoriasis. Vascular endothelial growth factor (VEGF), the most critical angiogenic factor, is thought to play important roles during the pathogenesis of psoriasis and may be a promising target for treating psoriasis. Therefore, we proposed that targeting VEGF/VEGFRs could lead to new treatments for psoriasis.
Vascular endothelial growth factor driving aberrant keratin expression pattern contributes to the pathogenesis of psoriasis.
Jiang Man,Li Bing,Zhang Jieyu,Hu Lei,Dang Erle,Wang Gang
Experimental cell research
Psoriasis is a chronic inflammatory skin disease severely affecting patients' physical and psychological well-being. Aberrant keratin expression in psoriasis plays a crucial role in keratinocyte dysfunction and disease development. Little is yet known about the mechanism of this keratin dysregulation. VEGF (Vascular endothelial growth factor) is significantly elevated in psoriatic patients and VEGFRs are detected on keratinocytes, leading to our hypothesis that this keratin dysregulation may be regulated by VEGF. In this study, we showed that VEGFR2 was overexpressed in psoriatic epidermis and was correlated with K (keratin) 6, K16&K17 upregulation and K1&K10 downregulation. VEGF increased both mRNA and protein levels of K6, K16&K17 and decreased those of K1&K10 in NHEKs (normal human epidermal keratinocytes). Further we identified activation of STAT3, ERK1/2, and p38 pathways in VEGF-treated NHEKs. Using specific pathway antagonists and siRNAs we found that VEGF induced K6, K16&K17 via these three pathways and reduced K1&K10 via ERK1/2. Finally, VEGF-induced aberrant keratin expression pattern and epidermal thickening were confirmed in a VEGF-local-injection mouse model. Collectively, we demonstrated that VEGF was associated with aberrant keratin expression pattern in psoriasis and provided a new insight into the role of VEGF in psoriasis pathogenesis, indicating VEGF as a potential therapeutic target.
IMQ Induced K14-VEGF Mouse: A Stable and Long-Term Mouse Model of Psoriasis-Like Inflammation.
Wang Xuguo,Sun Jun,Hu JinHong
An imiquimod (IMQ) induced wild type (WT) mouse can mimic some features of psoriasis, such as thickened skin, abnormal keratinocyte-related proteins, infiltration of inflammatory cells and pro-inflammatory cytokines. This model is a prevalent model that is widely used in the study of psoriasis. However, skin inflammation decreases during the eighth day when IMQ is given to WT mice, which may result in false results when evaluating the pharmacodynamics effects of a drug. To extend the timeliness and inherit the advantages of this model, we applied IMQ to the skin of 8-week-old homozygous K14-VEGF mice to investigate whether IMQ can prolong mice ear inflammation. In our experiments, we found that, compared to the IMQ induced WT mice model, the IMQ induced K14-VEGF mice have serious skin inflammation, even on the fourteenth day. We also evaluated the stability of skin inflammation at days 8, 10, and 13, and the inflammatory situation remained stable in the skin. This research intends to improve the existing model, and we hypothesize that the IMQ induced K14-VEGF mouse will become a practical mouse model in psoriasis research.
Correlation of expression of STAT3, VEGF and differentiation of Th17 cells in psoriasis vulgaris of guinea pig.
Zheng Xiu-Fen,Sun Yue-Dong,Liu Xue-Yan
Asian Pacific journal of tropical medicine
OBJECTIVE:To investigate the role of T help 17 cells (Th17) and STAT3-VEGF pathway in pathogenesis of psoriasis. METHODS:A total of 50 cases of psoriasis guinea pigs and 20 normal guinea pigs were selected. The ratio of Th17/ IL-17 cell in peripheral blood were detected by flow cytometric analysis; STAT3 and VEGF concentrations were measured by immunohistochemistry and Western blot. RESULTS:The expression of Th17 in peripheral blood were significantly increased in psoriasis [(1.76±0.88)%] compared with controls [(0.48±0.27)%] (P<0.05). Th17 related cytokine STAT3 and VEGF were significantly increased in psoriasis compared with controls (P<0.05), and were positively correlated the expression of Th17. CONCLUSIONS:The expressions of Th17, STAT3 and VEGF are elevated in psoriasis, which suggests Th17 cells have a potential role in the pathogenesis of psoriasis by STAT3-VEGF pathway.
Comparative expression of PEDF and VEGF in human epidermal keratinocytes and dermal fibroblasts: from normal skin to psoriasis.
Yan Bing-Xi,Zheng Yu-Xin,Li Wei,Chen Jia-Qi,Zhou Jiong,Cai Sui-Qing,Zheng Min,Man Xiao-Yong
Vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) have been shown to keep angiogenesis activation and inhibition in balance in normal and pathological conditions. In this study, we examined the expression of VEGF and PEDF in keratinocytes and fibroblasts from normal and psoriatic skin to evaluate their potential roles and interactions in the development of psoriasis. The expression of VEGF and PEDF was detected in normal and psoriatic skin ex vivo and in co-cultured keratinocytes and fibroblasts in vitro, and increased in keratinocytes and fibroblasts from psoriatic skin compared with those cells from normal skin. Our results suggest that PEDF act as a multipotent factor in the skin and the imbalance of PEDF and VEGF may be responsible for the transformation from normal skin to psoriasis.
Ectodomain Shedding of Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE-1) Is Induced by Vascular Endothelial Growth Factor A (VEGF-A).
Nishida-Fukuda Hisayo,Araki Ryoichi,Shudou Masachika,Okazaki Hidenori,Tomono Yasuko,Nakayama Hironao,Fukuda Shinji,Sakaue Tomohisa,Shirakata Yuji,Sayama Koji,Hashimoto Koji,Detmar Michael,Higashiyama Shigeki,Hirakawa Satoshi
The Journal of biological chemistry
Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a type I transmembrane glycoprotein, is known as one of the most specific lymphatic vessel markers in the skin. In this study, we found that the ectodomain of LYVE-1 undergoes proteolytic cleavage, and this process produces soluble LYVE-1. We further identified the cleavage site for ectodomain shedding and generated an uncleavable mutant of LYVE-1. In lymphatic endothelial cells, ectodomain shedding of LYVE-1 was induced by vascular endothelial growth factor (VEGF)-A, an important factor for angiogenesis and lymphangiogenesis under pathological conditions. VEGF-A-induced LYVE-1 ectodomain shedding was mediated via the extracellular signal-regulated kinase (ERK) and a disintegrin and metalloproteinase (ADAM) 17. Wild-type LYVE-1, but not uncleavable LYVE-1, promoted migration of lymphatic endothelial cells in response to VEGF-A. Immunostaining analyses in human psoriasis skin lesions and VEGF-A transgenic mouse skin suggested that the ectodomain shedding of LYVE-1 occurred in lymphatic vessels undergoing chronic inflammation. These results indicate that the ectodomain shedding of LYVE-1 might be involved in promoting pathological lymphangiogenesis.
Silencing KRT16 inhibits keratinocyte proliferation and VEGF secretion in psoriasis via inhibition of ERK signaling pathway.
Chen Jin-Guang,Fan Hua-Yu,Wang Ting,Lin Lan-Ying,Cai Tian-Guo
The Kaohsiung journal of medical sciences
Psoriasis is a multisystem disease affecting about 2% of the population, while keratin16 (KRT16) has been reported to participate in psoriasis. However, the specific mechanism of KRT16 in psoriasis was inadequately investigated. The objective of the study was to elucidate the mechanism by which siRNA-mediated silencing of KRT16 affects keratinocyte proliferation and vascular endothelial growth factor (VEGF) secretion in psoriasis through the extracellular signal-related kinase (ERK) signaling pathway. Psoriasis-related core gene KRT16 was screened out. Then, the expression of KRT16, VEGF, and ERK signaling pathway-related genes was detected in psoriatic patients. To further investigate the mechanism of KRT16, keratinocytes in psoriatic patients were treated with KRT16 siRNA or/and ERK inhibitor (PD98059) to detect the changes in related gene expression and cell survival. KRT16 was involved in psoriasis development. The expression levels of KRT16, p-ERK1/2, and VEGF in lesion tissues are significantly elevated. Keratinocytes treated with KRT16-siRNA and KRT16-siRNA + PD98059 exhibited reduced KRT16, p-ERK1/2, and VEGF expression. The cell survival rate in cells treated with KRT16-siRNA, PD98059, and KRT16-siRNA + PD98059 reduced significantly. These findings indicate that silencing KRT16 inhibits keratinocyte proliferation and VEGF secretion in psoriasis via inhibition of ERK signaling pathway, which provides a basic theory in the treatment of psoriasis.