Macrophage migration inhibitory factor may contribute to vasculopathy in systemic sclerosis.
Becker Heidemarie,Willeke Peter,Schotte Heiko,Domschke Wolfram,Gaubitz Markus
Increasing evidence supports the concept of macrophage migration inhibitory factor (MIF) as a central proinflammatory cytokine in autoimmune diseases. To further evaluate its role in systemic sclerosis (SSc), serum levels of MIF were determined by enzyme-linked immunoassay, and correlations to clinical manifestations were analyzed in 43 patients. MIF levels were significantly increased in patients (median, 18.8; range, <0.015-189 ng/ml) in comparison to healthy controls (n=43, 8.0, <0.015-36.5 ng/ml; P<0.0005). MIF values were higher in diffuse than in limited cutaneous SSc (P<0.005). Patients with pulmonary hypertension and recurrent digital ulcers showed higher MIF levels than patients without these manifestations (P<0.005). This association was also observed in limited cutaneous SSc. Sequential studies revealed decreased MIF levels after initiation of immunosuppressive therapy. MIF levels were not significantly different in patients with and without macrovascular disease of the peripheral arteries. The results suggest that MIF might contribute to inflammation and vasculopathy in SSc.
Correlation between genetic susceptibility of tuberculosis and macrophage migration inhibitory factor.
Wang Y L,Zhang C X,Shi G C,Zhang Q Y,Liu W G
Journal of biological regulators and homeostatic agents
This paper aims to study the relationship between genetic susceptibility of tuberculosis and macrophage migration inhibitory factor (MIF) and provide theoretical basis and foundation for further studies on pathogenesis and treatment of tuberculosis. Enzyme Linked Immuno Sorbent Assay (ELISA) was applied to detect the difference of MIF protein expression level in peripheral serum of the test subjects, and analyze the difference of MIF protein expression levels of different genotypes and alleles at -794CATT locus and -173G/C locus. The results showed that MIF protein expression level in serum of patients in the tuberculosis group was higher than that of the healthy control group (p < 0.05). The MIF protein expression level of genotype (5/5+5/6+6/6) and (7/X+8/X) at -794CATT locus of the tuberculosis group was higher than that of the healthy control group (p < 0.05), and MIF protein expression level of genotype GG and (GC+CC) at -173G/C locus of the tuberculosis group was higher than that of the healthy control group (p < 0.05). Therefore, macrophage migration inhibitory factor is an important cell factor which plays a regulating role in the immune system, as it can inhibit macrophage migration and promote the gathering, infiltration and proliferation of macrophages at inflammatory sites. Furthermore, it can secrete some cell factors which play a central role in immunological regulation.
Macrophage migration inhibitory factor in patients with vitiligo and relationship between duration and clinical type of disease.
Serarslan G,Yönden Z,Söğüt S,Savaş N,Celik E,Arpaci A
Clinical and experimental dermatology
BACKGROUND:Vitiligo is a disorder of pigmentation characterized by the presence of depigmented skin macules. Cellular immunity is known to have a role in the pathogenesis of vitiligo. Macrophage migration inhibitory factor (MIF) is a potent activator of macrophages and is considered to play an important role in cell-mediated immunity. AIMS:To determine serum level of MIF in patients with vitiligo and compare with healthy controls. We also aimed to determine whether there is a relationship between MIF levels and the disease duration, clinical vitiligo and involved body surface area (BSA) in patients with vitiligo. METHODS:The study group comprised 30 patients with vitiligo (14 men, 16 women) and 30 healthy controls, matched for age and gender. Blood samples were taken for MIF analysis. RESULTS:The mean serum level of MIF in patients with vitiligo (40.83 +/- 31.66 pg/mL) was significantly higher than that of the control group (21.00 +/- 6.48 pg/mL) (P = 0.002). There was a positive correlation between disease duration and MIF levels (r = 0.601, P < 0.001). Mean MIF level of patients with acral and acrofacial vitiligo (n = 6) was 48.25 +/- 32.02 pg/mL, and of patients generalized vitiligo (n = 18) was 44.46 +/- 35.25 pg/mL. There was no significant difference between these two groups (P > 0.05). However there was a significant difference in MIF levels between patients with localized (20.41 +/- 5.23, n = 5) and acral-acrofacial (P = 0.02) vitiligo and those with generalized (P = 0.006) vitiligo. There was no relationship between BSA and MIF levels. CONCLUSIONS:Mean serum MIF level of patients with vitiligo was higher than that of controls, indicating that MIF has a role in the pathogenesis of vitiligo.
Serum levels of macrophage migration inhibitory factor are associated with rheumatoid arthritis course.
Llamas-Covarrubias Mara Anaís,Valle Yeminia,Navarro-Hernández Rosa Elena,Guzmán-Guzmán Iris Paola,Ramírez-Dueñas María Guadalupe,Rangel-Villalobos Héctor,Estrada-Chávez Ciro,Muñoz-Valle José Francisco
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease of unknown etiology. Many cytokines have been found to be associated with RA pathogenesis and among them is macrophage migration inhibitory factor (MIF). The aim of this study was to determine whether MIF serum levels are associated with RA course, clinical activity, and clinical biomarkers of the disease. MIF levels were determined in serum samples of 54 RA patients and 78 healthy subjects (HS) by enzyme-linked immunosorbent assay (ELISA). Disease activity was evaluated using the DAS28 score. Patients were subgrouped according to disease activity and years of evolution of disease. Statistical analysis was carried out by SPSS 10.0 and GraphPad Prism 5 software. RA patients presented increased levels of MIF as compared to HS. MIF levels were raised on early stages of RA and tend to decrease according to years of evolution. Moreover, MIF levels positively correlated with rheumatoid factor in RA patients and with C reactive protein in all individuals studied. Our findings suggest that MIF plays a role in early stages of RA.
Macrophage migration inhibitory factor -173 G>C single nucleotide polymorphism and its association with active pulmonary tuberculosis.
Gehlen Mirela,Costa Elis Regina Dalla,Rossetti Maria Lucia Rosa,Silva Denise Rossato
PURPOSE:The establishment of candidate genes associated with susceptibility to TB is a challenge especially due to divergent frequencies among different populations. The objective of this study was to evaluate the association between macrophage migration inhibitory factor (MIF) -173 G>C single nucleotide polymorphism (SNP) and susceptibility to pulmonary TB in a population of southern Brazil. METHODS:Case-control study. Patients > 18 years old, diagnosed with pulmonary TB were included. The control group consisted of blood donors and household contacts, not relatives, healthy and > 18 years old. MIF -173 G>C SNPs were genotyped using real-time PCR using a TaqMan SNP Genotyping assay. RESULTS:174 patients and 166 controls were included. There were no statistically significant differences between cases and controls regarding genotype prevalence (p>0.05). Comparing patients with normal genotype (GG) with those with at least one C allele, there was also no statistically significant difference (p = 0.135). Also, there was no statistically significant difference comparing the homozygous for the mutation (CC) with the other patients (GG and CG) (p = 0.864). CONCLUSIONS:We did not find association between MIF -173 G>C polymorphism and susceptibility to pulmonary TB.
Macrophage migration inhibitory factor promoter polymorphisms (-794 CATT 5-8 and -173 G>C): relationship with mRNA expression and soluble MIF levels in young obese subjects.
Matia-García Inés,Salgado-Goytia Lorenzo,Muñoz-Valle José F,García-Arellano Samuel,Hernández-Bello Jorge,Salgado-Bernabé Aralia B,Parra-Rojas Isela
We analyzed the relationship of -794 CATT5-8 and -173 G>C MIF polymorphisms with mRNA and soluble MIF in young obese subjects. A total of 250 young subjects, 150 normal-weight and 100 obese subjects, were recruited in the study. Genotyping of -794 CATT5-8 and -173 G>C MIF polymorphisms was performed by PCR and PCR-RFLP, respectively. MIF mRNA expression was determined by real-time PCR and serum MIF levels were measured using an ELISA kit. For both MIF promoter polymorphisms, no significant differences in the genotype and allele frequencies between groups were observed. MIF mRNA expression was slightly higher in obese subjects than in normal-weight subjects (1.38-fold), while soluble MIF levels did not show differences between groups. In addition, we found an increase in MIF mRNA expression in carriers of the 6,6 and C/C genotypes and the 6G haplotype of the -794 CATT5-8 and -173 G>C MIF polymorphisms, although it was not significant. In conclusion, this study found no relationship between obesity and MIF gene promoter polymorphisms with MIF mRNA expression in young obese subjects.
Functional and prognostic relevance of -173 G/C gene polymorphism of macrophage migration inhibitory factor in sepsis patients in Egyptian intensive care units.
Meawed T E,Mansour M A,Mansour S A,Mohamed M L,Ibrahim E M,Ali A M
Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit
This study aimed to evaluate the association of plasma MIF level and -173 G/C single nucleotide polymorphism of the MIF gene with the occurrence, severity and mortality of sepsis patients. A study was conducted in adult surgical intensive care units of Zagazig University Hospitals, Egypt on 25 patients with sepsis, 27 with severe sepsis and 28 controls. Gram-negative bacilli were the most common isolates in both severe sepsis (63.0%) and sepsis (56.0%) patients. A highly statistically significant difference was found in MIF levels between sepsis cases and controls and a statistically significant difference as regards MIF level in different genotypes of the studied groups. MIF level was significantly associated with mortality in sepsis cases. High MIF levels and MIF -173G/C gene polymorphism are powerful predictors of the severity of sepsis and its outcome.
Macrophage Migration Inhibitory Factor -173 G>C Gene Polymorphism Is Associated with Increased Risk of Nephrotic Syndrome in Children.
Sadeghi-Bojd Simin,Falsafinejad Fariba,Danesh Hiva,Bizhani Fatemeh,Bahari Gholamreza,Hashemi Mohammad
Iranian journal of kidney diseases
INTRODUCTION:Nephrotic syndrome (NS), a common chronic pediatrickidney disease, is associated with immune system dysfunction.The exact role of MIF -137 G>C gene polymorphism on risk of NSis not clear. The current study aimed to evaluate the relationshipbetween MIF -173 G>C (rs755622) variant and susceptibility to NS. METHODS:This case-control study conducted on 134 children withNS and 141 healthy children. Extraction of genomic DNA fromwhole blood was done using salting out method. Genotyping ofthe MIF -173 G>C polymorphism was performed using polymerasechain reaction restriction fragment length polymorphism (PCRRFLP)method. RESULTS:The findings showed that MIF -173 G>C variant significantlyincreases the risk of NS in codominant (OR = 1.82, 95%CI = 1.08-3.08, P = 0.026, GC vs GG), dominant (OR = 1.90, 95%CI = 1.14-3.16,P = 0.015, GC+CC vs GG), overdominant (OR = 1.75, 95%CI = 1.04-2.94, P = 0.037, GC vs GG+CC) and allele (OR = 1.76, 95%CI = 1.13-2.74, P = 0.014, C vs G) inheritance models. Stratified analysisperformed by sex and response to treatment. The findings revealedthat this variant was associated with increased risk of NS in male.No correlation between the variant and response to treatment wasfound. CONCLUSION:In summary, the results indicated that MIF -137 G>Cis significantly associated with increased risk of NS. More studieswith larger sample size among different ethnicities are needed toverify our findings.
Serum and salivary macrophage migration inhibitory factor in patients with oral squamous cell carcinoma.
DE Souza Mariana Barbosa,Curioni Otávio Alberto,Kanda Jossi Ledo,DE Carvalho Marcos Brasilino
The overexpression of macrophage migration inhibitory factor (MIF) has been identified in a variety of tumors and the investigation of its molecular mechanisms in tumor progression is a key topic of research. The present study aimed to investigate MIF as a potential marker for disease control or recurrence, and to assess the association between serum and salivary MIF and the clinicopathological characteristics of patients with oral squamous cell carcinoma (OSCC). Serum and salivary samples were collected prior to and following the surgical treatment of 50 patients with OSCC. MIF concentrations were assessed by enzyme-linked immunosorbent assay and the adopted level of statistical significance was P<0.05. The results revealed that serum MIF concentrations were significantly reduced following tumor resection in OSCC patients. Furthermore, higher preoperative salivary MIF concentrations were observed in patients with larger tumors and in those who succumbed to the disease. In conclusion, high salivary and serological MIF concentrations were identified in patients with OSCC. Nevertheless, only serological MIF concentrations may be considered as a potential marker for the early detection of OSCC recurrence once the salivary levels, prior and following treatment, do not show any significant differences.
Macrophage Migration Inhibitory Factor -173 G/C Polymorphism: A Global Meta-Analysis across the Disease Spectrum.
Illescas Oscar,Gomez-Verjan Juan C,García-Velázquez Lizbeth,Govezensky Tzipe,Rodriguez-Sosa Miriam
Frontiers in genetics
Human macrophage migration inhibitory factor (MIF) is a cytokine that plays a role in several metabolic and inflammatory processes. Single nucleotide polymorphism (SNP) -173 G/C (rs755622) on gene has been associated with numerous diseases, such as arthritis and cancer. However, most of the reports concerning the association of MIF with these and other pathologies are inconsistent and remain quite controversial. Therefore, we performed a meta-analysis from 96 case-control studies on -173 G/C SNP and stratified the data according to the subjects geographic localization or the disease pathophysiology, in order to determine a more meaningful significance to this SNP. The polymorphism was strongly associated with an increased risk in autoimmune-inflammatory, infectious and age-related diseases on the dominant (OR: 0.74 [0.58-0.93], < 0.01; OR: 0.81 [0.74-0.89], < 0.0001; and OR: 0.81 [0.76-0.87], < 0.0001, respectively) and the recessive models (OR: 0.74 [0.57-0.095], < 0.01; OR: 0.66 [0.48-0.92], < 0.0154; and OR: 0.70 [0.60-0.82], < 0.0001, respectively). Also, significant association was found in the geographic localization setting for Asia, Europe and Latin America subdivisions in the dominant (OR: 0.76 [0.69-0.84], < 0.0001; OR: 0.77 [0.72-0.83], < 0.0001; OR: 0.61 [0.44-0.83], -value: 0.0017, respectively) and overdominant models (OR: 0.85 [0.77-0.94], < 0.0001; OR: 0.80 [0.75-0.86], < 0.0001; OR: 0.73 [0.63-0.85], -value: 0.0017, respectively). Afterwards, we implemented a network meta-analysis to compare the association of the polymorphism for two different subdivisions. We found a stronger association for autoimmune than for age-related or autoimmune-inflammatory diseases, and stronger association for infectious than for autoimmune-inflammatory diseases. We report for the first time a meta-analysis of rs755622 polymorphism with a variety of stratified diseases and populations. The study reveals a strong association of the polymorphism with autoimmune and infectious diseases. These results may help direct future research on -173 G/C in diseases in which the relation is clearer and thus assist the search for more plausible applications.
Association study between macrophage migration inhibitory factor-173 polymorphism and acute myeloid leukemia in Taiwan.
Ramireddy Latha,Lin Chien-Yu,Liu Su-Ching,Lo Wan-Yu,Hu Rouh-Mei,Peng Yi-Chin,Peng Ching-Tien
Cell biochemistry and biophysics
Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays a significant role in pathogenesis and autoimmune diseases. The major function of MIF is to promote the cell proliferation, migration, and invasion. The aim of the present study is to identify the association between MIF-173 (rs755662) single nucleotide polymorphism (SNP) and AML in Taiwanese population. DNA samples extracted from 256 AML patients and 256 healthy controls were investigated using polymerase chain reaction followed by restriction fragment length polymorphism analysis. The association between MIF-173 SNP genotype and AML patients were assessed with SPSS software. The results show that the GC genotype of MIF-173 SNP is significantly higher in AML patients than in the healthy controls (OR 1.58, 95 % CI 1.06, P = 0.034). Carrier genotypes GC and CC may be a causative factor for AML cancer (OR 1.39, 95 % CI 0.95, P = 0.085). White blood cell count (10(3)/µl) were significantly associated with AML MIF-173 polymorphism patients (P = 0.002). Our results in this study provide the first evidence that the MIF-173 polymorphism is associated with AML. MIF is a potential biomarker for development of AML cancer in male adult in Taiwanese population. Further validations in other populations are warranted.
The Relationship between Functional Promoter Variants of Macrophage Migration Inhibitory Factor and Endometriosis.
Chekini Zahra,Shahhoseini Maryam,Aflatoonian Reza,Afsharian Parvaneh
Objective:Endometriosis is a common gynecological and inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine that is secreted by accumulated active macrophages in ectopic endometrial tissues. Two promoter polymorphisms of [-794(CATT) /-173G/C] were identified to susceptibility and severity of several immune and inflammatory diseases. We aimed to evaluate the possible association between promoter polymorphisms and susceptibly to endometriosis and its corolation with mRNA level. Materials and Methods:This case-control study was performed in Royan Institute from 2015 to 2017. Polymorphisms were evaluated in 106 endometriosis patients and 110 controls. For 17 endometrioma tissues, gene expression studies were conducted during secretory phase of menstrual cycle. Restriction fragment length polymorphism (RFLP) analysis was performed to determine -173G/C polymorphism and -794(CATT) were detected by sequencing. Quantitative polymerase chain reaction (Q-PCR) was carried out to determine MIF expression level. Results:Homozygote of CATT was observed only in endometriosis whilst we did not detect the significant allele and genotype variation in both groups. The homozygotes for -794(CATT) and -173G/C polymorphisms were obtained to estimate the haplotype frequencies. Significantly higher haplotype frequencies were observed for CATT/G in controls [global P value=0.044]. Additionally, the CATT/C and CATT/G haplotypes were not detected in any groups. Expression level of mRNA in ectopic tissue of endometriosis patients with CATT/CC haplotype, were significantly higher compared to other haplotypes including CATT/GG (2.91 fold, P=0.007), CATT/GC (2.48 fold, P=0.047) and CATT/GG (2.08 fold, P=0.046). Conclusion:We report, for the first time, a strong linkage between the decreased repetition of CATT and G allele in control and CATT/C and CATT/C haplotypes in endometriosis patients. Increased MIF expression is affected by genetic variants in the promoter in ectopic endometrial tissues. This promoter haplotype might play an important role in the development and establishment of endometriosis.
Relationship of macrophage migration inhibitory factor levels in PBMCs, lesional skin and serum with disease severity and activity in vitiligo vulgaris.
Ma Lei,Xue Hai-Bo,Guan Xiu-Hao,Shu Chun-Mei,Zhang Yu-Jie,Zhang Jun-Hua,An Rong-Zhen
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
Melanocyte loss in vitiligo vulgaris is believed to be an autoimmune process. Macrophage migration inhibitory factor (MIF) is involved in many autoimmune skin diseases. We determined the possible role of MIF in the pathogenesis of vitiligo vulgaris, and describe the relationship between MIF expressions and disease severity and activity. Serum MIF concentrations and mRNA levels in PBMCs were measured in 44 vitiligo vulgaris patients and 32 normal controls, using ELISA and real-time RT-PCR. Skin biopsies from 15 patients and 6 controls were analyzed by real-time RT-PCR. Values are reported as median (25th-75th percentile). Serum MIF concentrations were significantly increased in patients [35.81 (10.98-43.66) ng/mL] compared to controls [7.69 (6.01-9.03) ng/mL]. MIF mRNA levels were significantly higher in PBMCs from patients [7.17 (3.59-8.87)] than controls [1.67 (1.23-2.42)]. There was also a significant difference in MIF mRNA levels in PBMCs between progressive and stable patients [7.86 (5.85-9.13) vs 4.33 (2.23-8.39)] and in serum MIF concentrations [40.47 (27.71-46.79) vs 26.80 (10.55-36.07) ng/mL]. In addition, the vitiligo area severity index scores of patients correlated positively with changes of both serum MIF concentrations (r = 0.488) and MIF mRNA levels in PBMCs (r = 0.426). MIF mRNA levels were significantly higher in lesional than in normal skin [2.43 (2.13-7.59) vs 1.18 (0.94-1.83)] and in patients in the progressive stage than in the stable stage [7.52 (2.43-8.84) vs 2.13 (1.98-2.64)]. These correlations suggest that MIF participates in the pathogenesis of vitiligo vulgaris and may be useful as an index of disease severity and activity.
Association of macrophage migration inhibitory factor promoter polymorphism -173G/C with susceptibility to childhood asthma.
El-Adly Tarek Z,Kamal Sally,Selim Hala,Botros Shahira
Central-European journal of immunology
INTRODUCTION:Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in the pathogenesis of asthma. Polymorphisms associated with inflammatory diseases exist in the promoter region of MIF, which alter its expression. We aimed to study the association of MIF promoter polymorphism -173G/C with childhood asthma. MATERIAL AND METHODS:In this case-control study, we recruited 60 pediatric patients with bronchial asthma and 90 age- and sex-matched healthy controls. MIF-173G/C was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS:Genotype distribution between cases and healthy controls was statistically evaluated. Our results revealed that the frequency of the MIF-173C allele was significantly higher in children with asthma than in the control group (p = 0.002, odds ratio [OR] = 3.61, 95% confidence interval [CI] = 1.63-7.97). The frequency of the MIF-173CC genotype was higher in the asthmatic children than in the controls (p = 0.028, OR = 6.24, 95% CI = 1.24-31.29). Comparing carriage of the MIF-173C allele in pediatric patients with asthma with that observed in healthy controls (GC + CC vs. GG) revealed a positive association with the disease (p = 0.019, OR = 3.12, 95% CI = 1.22-7.99). CONCLUSIONS:These results suggest that MIF-173G/C polymorphism confers an increased risk of susceptibility to the development of childhood asthma in an Egyptian population.
Association between macrophage migration inhibitory factor in the endometrium and estrogen in endometriosis.
Zhang Xiao,Mu Lin
Experimental and therapeutic medicine
Recent studies have shown that macrophage migration inhibitory factor (MIF) has a possible role in endometriosis-related pain and infertility, yet it has not been explored whether the mRNA level of MIF is altered in endometrial tissues from patients with endometriosis. The aim of the present study was to compare the expression of MIF in endometrial tissues from women with and without endometriosis, and to analyze the association between endometrial MIF expression and 17β-estradiol (E). The protein and mRNA expression of MIF in the human endometrial tissue was assessed by western blotting and reverse transcription-polymerase chain reaction analysis, respectively. The MIF expression of women with endometriosis was found to be significantly higher than that of the controls. A positive correlation was noted between the serum E level and MIF expression. In endometrial cells from women with endometriosis, the level of E-induced MIF upregulation was significantly higher than that in cells from women without endometriosis. In conclusion, this study demonstrated a significant increase in MIF expression in the endometrial tissues of women with endometriosis and an association between MIF expression and E level. MIF expression in endometrial cells from patients with endometriosis showed an increased sensitivity to stimulation by E.
Macrophage Migration Inhibitory Factor in Acute Adipose Tissue Inflammation.
Kim Bong-Sung,Rongisch Robert,Hager Stephan,Grieb Gerrit,Nourbakhsh Mahtab,Rennekampff Hans-Oliver,Bucala Richard,Bernhagen Juergen,Pallua Norbert
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in inflammatory diseases. However, little is known about the regulation of MIF in adipose tissue and its impact on wound healing. The aim of this study was to investigate MIF expression in inflamed adipose and determine its role in inflammatory cell recruitment and wound healing. Adipose tissue was harvested from subcutaneous adipose tissue layers of 24 healthy subjects and from adipose tissue adjacent to acutely inflamed wounds of 21 patients undergoing wound debridement. MIF protein and mRNA expression were measured by ELISA and RT-PCR. Cell-specific MIF expression was visualized by immunohistochemistry. The functional role of MIF in cell recruitment was investigated by a chemotaxis assay and by flow cytometry of labeled macrophages that were injected into Mif-/-and wildtype mice. Wound healing was evaluated by an in vitro scratch assay on human fibroblast monolayers. MIF protein levels of native adipose tissue and supernatants from acutely inflamed wounds were significantly elevated when compared to healthy controls. MIF mRNA expression was increased in acutely inflamed adipose tissue indicating the activation of MIF gene transcription in response to adipose tissue inflammation. MIF is expressed in mature adipocytes and in infiltrated macrophages. Peripheral blood mononuclear cell migration was significantly increased towards supernatants derived from inflamed adipose tissue. This effect was partially abrogated by MIF-neutralizing antibodies. Moreover, when compared to wildtype mice, Mif-/-mice showed reduced infiltration of labeled macrophages into LPS-stimulated epididymal fat pads in vivo. Finally, MIF antibodies partially neutralized the detrimental effect of MIF on fibroblast wound healing. Our results indicate that increased MIF expression and rapid activation of the MIF gene in fat tissue adjacent to acute wound healing disorders may play a role in cell recruitment to the site of inflammation and wound healing.
Macrophage migration inhibitory factor as a potential prognostic factor in gastric cancer.
He Long-Jun,Xie Dan,Hu Pin-Jin,Liao Yi-Ji,Deng Hai-Xia,Kung Hsiang-Fu,Zhu Sen-Lin
World journal of gastroenterology
AIM:To investigate macrophage migration inhibitory factor (MIF) expression and its clinical relevance in gastric cancer, and effects of MIF knockdown on proliferation of gastric cancer cells. METHODS:Tissue microarray containing 117 samples of gastric cancer and adjacent non-cancer normal tissues was studied for MIF expression by immunohistochemistry (IHC) semiquantitatively, and the association of MIF expression with clinical parameters was analyzed. MIF expression in gastric cancer cell lines was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Two pairs of siRNA targeting the MIF gene (MIF si-1 and MIF si-2) and one pair of scrambled siRNA as a negative control (NC) were designed and chemically synthesized. All siRNAs were transiently transfected in AGS cells with Oligofectamine(TM) to knock down the MIF expression, with the NC group and mock group (Oligofectamine(TM) alone) as controls. At 24, 48, and 72 h after transfection, MIF mRNA was analyzed by RT-PCR, and MIF and proliferating cell nuclear antigen (PCNA) proteins were detected by Western blot. The proliferative rate of AGS cells was assessed by methylthiazolyl tetrazolium (MTT) assay and colony forming assay. RESULTS:The tissue microarray was informative for IHC staining, in which the MIF expression in gastric cancer tissues was higher than that in adjacent non-cancer normal tissues (P < 0.001), and high level of MIF was related to poor tumor differentiation, advanced T stage, advanced tumor stage, lymph node metastasis, and poor patient survival (P < 0.05 for all). After siRNA transfection, MIF mRNA was measured by real-time PCR, and MIF protein and PCNA were assessed by Western blot analysis. We found that compared to the NC group and mock group, MIF expression was knocked down successfully in gastric cancer cells, and PCNA expression was downregulated with MIF knockdown as well. The cell counts and the doubling times were assayed by MTT 4 d after transfection, and colonies formed were assayed by colony forming assay 10 d after transfection; all these showed significant changes in gastric cancer cells transfected with specific siRNA compared with the control siRNA and mock groups (P < 0.001 for all). CONCLUSION:MIF could be of prognostic value in gastric cancer and might be a potential target for small-molecule therapy.
Serum macrophage migration inhibitory factor is correlated with atrial fibrillation.
Wan Chunfu,Li Zhihua
Journal of clinical laboratory analysis
OBJECTIVE:Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine secreted by macrophages. This study is performed to investigate whether serum MIF is correlated with atrial fibrillation (AF). METHODS:Totally, 186 AF patients and 103 healthy controls were enrolled in this study. AF patients were then divided into paroxysmal AF, persistent AF, and permanent AF subgroups. RESULTS:There were higher serum MIF concentrations in AF patients than in healthy subjects. Logistic regression analysis demonstrated that serum MIF was associated with AF. Permanent AF patients exhibited higher serum MIF concentrations than persistent and paroxysmal AF subgroups. Elevated serum MIF concentrations were found in persistent AF patients compared with paroxysmal AF patients. Moreover, serum MIF concentrations were associated with left atrial diameter after Spearman correlation analysis.
Assessment of macrophage migration inhibitory factor in patients with verruca vulgaris.
Sorour Neveen Emad,Hamed Ahmed Mohamed,Tabl Hala Abd-El Mageed,Ahmed Amira Abd-El Aziz
Clinical, cosmetic and investigational dermatology
Background:Common warts are caused by human papillomaviruses (HPVs), they are among the most common cutaneous viral infections. Macrophage migration inhibitory factor (MIF) is an essential contributor in many inflammatory and immune skin diseases. Yet, its role in the pathology of common warts is unclear. Objective:To assess MIF levels in lesional and perilesional skin in patients with common warts in comparison to apparently healthy control group with matching age and sex. Subjects and methods:A case-control study performed on 60 patients with common warts (group A) and 30 age and sex matching healthy controls (group B). Two biopsies were taken from each patient in group A; one from the lesion (lesional) and the other one from the skin around the wart (perilesional), while biopsies of controls were taken from matched sites to patients. Measurement of MIF in all groups was done by quantitative ELISA kits. Results:Significant high MIF levels were detected in lesional and perilesional skin biopsies compared to controls (<0.001). Yet, the difference in MIF levels between lesional and perilesional skin biopsy was non-significant. No significant relations were found between lesional and perilesional MIF levels and clinical characteristics of the studied patients while both lesional and perilesional MIF levels were significantly correlated (rh=0.269, =0.021). Conclusion:The significantly elevated MIF levels in lesional and perilesional skin biopsies compared to controls point to its role in wart progression from HPV infected cells.
Association of MIF promoter polymorphisms with childhood asthma in a northeastern Chinese population.
Wu J,Fu S,Ren X,Jin Y,Huang X,Zhang X,Bai J,Fu S
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays an important role in pathogenesis of asthma. A high level of MIF has been detected in bronchoalveolar lavage fluid, serum and sputum in asthma. Polymorphisms associated with inflammatory diseases exist in the promoter region of MIF, which alter its expression. The aim of this study was to evaluate the potential relationship between functional polymorphisms of MIF and childhood asthma in a northeastern Chinese population. The study consisted of a set of 41 trios and an independent sample set of 189 childhood asthma patients and 261 healthy controls. We genotyped MIF-173G/C using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Additionally, MIF-794CATT(5-8) microsatellite polymorphism was genotyped by polyacrylamide gel electrophoresis (PAGE). A statistically significant difference in the distribution of the MIF-173C allele between patients and controls [P = 0.01, odds ratio (OR) = 1.55, 95% confidence interval (CI) = 1.13-2.18] was observed. In addition, the frequency of the MIF-173CC genotype was higher in asthmatic children (P < 0.01, OR = 3.37, 95% CI = 1.27-8.93). No difference in the distribution of CATT(5-8) was found between patients and healthy controls. Haplotype analysis showed that only the MIFCATT(7)-173C haplotype was associated with greater susceptibility to childhood asthma (P = 0.03, OR = 1.54, 95% CI 1.03-2.28). However, the transmission disequilibrium test confirmed a positive association between MIF-173G/C and childhood asthma (P = 0.005), and the absence of an association between the MIF-794CATT(5-8) and the disease. These preliminary results suggest an association between the MIF-173C allele and childhood asthma.
A Macrophage Migration Inhibitory Factor Polymorphism Is Associated with Autoimmune Hepatitis Severity in US and Japanese Patients.
Assis David N,Takahashi Hiroki,Leng Lin,Zeniya Mikio,Boyer James L,Bucala Richard
Digestive diseases and sciences
BACKGROUND:The pathogenesis of autoimmune hepatitis (AIH) is incompletely understood. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine implicated in the pathophysiology of multiple autoimmune diseases. We recently reported that MIF expression was increased in a US AIH cohort. MIF expression in non-Western AIH patients is unknown. A MIF-173 GC single nucleotide polymorphism in the MIF promoter (rs755622) is clinically associated with steroid resistance in several inflammatory disorders but has not been evaluated in AIH. AIM:To compare MIF polymorphisms and their relationship to clinical parameters in AIH patients from the USA and Japan. METHODS:DNA and matched sera from AIH patients and healthy controls from Japan (N = 52) were compared to the US group. Serum concentrations of MIF and its circulating receptor CD74 were measured by ELISA. MIF-173 GC (rs755622) and MIF-794 CATT (rs5844572) polymorphisms were analyzed by standard methods. MIF genotypes were correlated with serum ALT and steroid requirements. RESULTS:Serum MIF was increased in Japanese AIH patients versus local controls, in agreement with the US AIH patients. Within both AIH groups, ALT was higher in CC/GC versus GG patients. Further, the steroid requirement was higher in AIH patients with GC/CC genotypes from both groups. In the Japanese patient group, the GC/CC genotype also was associated with acute symptomatic presentation. CONCLUSIONS:The MIF-173 CC/GC genotypes may be associated with both higher ALT and maintenance steroid requirements in AIH patients from the USA and Japan. This polymorphism could be a marker of disease severity in AIH patients.
Expression of macrophage migration inhibitory factor in keratitis.
Xu Qiang,Hu Li-Ting,Wang Qian,Lin Jing,Jiang Nan,Li Cui,Zhao Gui-Qiu
International journal of ophthalmology
AIM:To investigate the expression of macrophage migration inhibitory factor (MIF) and detect its role in the innate immune response of fungal keratitis (FK). METHODS:We collected the paraffin-embedded cornea tissues from 10 FK and 6 ocular trauma patients to explore the MIF expression by immunohistochemistry. Then we cultured telomease-immortalized human corneal epithelial cells (THCEs), stimulated by the hyphae suspension of () to detect the change of MIF with or without the pretreatment of MIF inhibitor [4-Iodo-6-phenylpyrimidine (4-IPP)] by real-time polymerase chain reaction (PCR). The protein level of MIF was also tested by immunohistochemistry, and the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA were compared between normal, hyphae stimulated and 4-IPP pretreated groups by real-time PCR to study the influence of MIF on the expression of TNF-α and IL-6. Corneal severity of rats' FK models was documented by clinical scores, and real-time PCR. Western blot and immunohistochemistry were used to test the expression of MIF, TNF-α and IL-6 in rats' corneas. RESULTS:In the corneas of FK patients, there was much stronger expression of MIF than that in the normal group showed by immunohistochemistry. In cultured THCEs stimulated by , the expression of MIF became stronger in both immunohistochemistry and PCR at 16, 24, 32 and 48h post infection (p.i.; <0.01, <0.01, <0.01, <0.05). After pretreated with 4-IPP, the expression of MIF reduced at 4, 8, 16h p.i. (<0.05, <0.05, <0.05) and the downstream TNF-α and IL-6 decreased obviously (<0.05, <0.01). In rats with keratitis, the relative mRNA and protein level of MIF increased than those in the normal group by PCR (at 1d: <0.01, 3d: <0.01, 5d: <0.01), Western blot and immunohistochemistry. After blocked MIF with 4-IPP, the clinical outcomes of rat keratitis showed markedly reduced inflammatory response (<0.01), with TNF-α and IL-6 decreased in accordance with those in THCEs by PCR (<0.05, <0.01). CONCLUSION:The expression of MIF increased significantly in FK patients, THCEs and rats stimulated by . After blocked with 4-IPP, the expression of MIF reduced, and so did its downstream cytokines: TNF-α and IL-6. The inflammation reaction of the rats' corneas lightened after pretreated with 4-IPP. MIF may play a role in the innate immune response of the corneal resistance against .
Circulating macrophage migration inhibitory factor levels and its polymorphisms in systemic lupus erythematosus: A meta-analysis.
Bae S-C,Lee Y H
Cellular and molecular biology (Noisy-le-Grand, France)
The present study aimed to systemically review the evidence regarding the relationship between circulating macrophage migration inhibitory factor (MIF) levels and systemic lupus erythematosus (SLE), as well as the associations between several polymorphisms in the MIF gene and SLE susceptibility. We performed a meta-analysis of serum/plasma levels of MIF in SLE patients and controls and evaluated evidence of associations between the MIF -173 C/G allele and -794CATT5-8 polymorphisms and the associated risk for SLE. Nine studies were included in this meta-analysis. Meta-analysis indicated that MIF levels were significantly higher in the SLE group than in the control group (SMD = 1.154, 95% CI = 0.369-1.938, P = 0.004). Stratification by ethnicity showed significantly higher MIF levels in the SLE group representing Asian populations (SMD = 1.911, 95% CI = 0.871-2.951, P < 0.001). MIF levels were significantly higher in the SLE group than in the control group in the age-and/or sex matched population, but not in the unmatched population (SMD = 1.236, 95% CI = 0.579-1.893, P < 0.001; SMD = 1.118, 95% CI = -0.027-2.263, P = 0.056). However, results of the meta-analysis showed no association between SLE and the MIF -173 C allele, the -794CATT7 allele, and the -794CATT7-MIF-173C haplotype with high heterogeneity. Our meta-analysis demonstrated significantly higher circulating MIF levels in patients with SLE, but no evidence of associations between MIF -173 C/G and -794CATT5-8 polymorphisms and SLE susceptibility.
Prognostic role of macrophage migration inhibitory factor expression in patients with squamous cell carcinoma of the lung.
Koh Hyun Min,Kim Dong Chul,Kim Yu-Min,Song Dae Hyun
BACKGROUND:Macrophage migration inhibitory factor (MIF) has been shown to play an important role in the inflammatory and immune response in squamous cell carcinoma (SCC). Recent studies have reported that MIF is involved in the tumorigenesis and overexpressed in various cancers. In this study, we assessed the prognostic role of MIF expression in SCC of the lung, and demonstrated the effect of knockdown of MIF on the migration in lung SCC cell lines. METHODS:The relationship between MIF expression and clinicopathological parameters and the prognostic role of MIF expression were evaluated with immunohistochemical staining in 96 patients with SCC of the lung. The expression of MIF mRNA and protein was analyzed by semi-quantitative polymerase chain reaction and Western blot in lung SCC cell. The effect of knockdown of MIF was assessed by wound healing assay. RESULTS:The high percentage of MIF-positive cells was significantly associated with lymph node metastasis (P = 0.004), and was a poor prognostic factor of disease-free survival (DFS) (hazard ratio [HR]: 3.125; 95% confidence interval [CI], 1.628-5.998; P = 0.001) and disease-specific survival (DSS) (HR: 2.303; 95% CI, 1.172-4.525; P = 0.016). Moreover, Kaplan-Meier analysis showed that SCC patients with a high percentage of MIF-positive cells had a significantly lower DFS (P = 0.001) and DSS (P = 0.014) than those with a low percentage. Furthermore, wound healing assay revealed that knockdown of MIF resulted in decreased cellular migration. CONCLUSION:MIF is closely associated with tumor progression and could be a prognostic factor in SCC of the lung.
Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia.
Okazaki Satoshi,Hishimoto Akitoyo,Otsuka Ikuo,Watanabe Yuichiro,Numata Shusuke,Boku Shuken,Shimmyo Naofumi,Kinoshita Makoto,Inoue Emiko,Ohmori Tetsuro,Someya Toshiyuki,Sora Ichiro
Progress in neuro-psychopharmacology & biological psychiatry
BACKGROUND:Numerous studies have suggested that an immune system imbalance plays an important role in schizophrenia. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine. It plays multiple roles in various biological processes, including inflammation and neurogenesis. Furthermore, several exhaustive serum proteomic profiling studies have identified MIF as a potential biomarker of schizophrenia. Here, we investigate MIF protein levels in serum and postmortem prefrontal cortex in patients with schizophrenia and controls. Moreover, we investigate the association of two functional polymorphisms in the MIF gene promoter region (MIF-794CATT microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) with schizophrenia. METHODS:We measured serum MIF levels with an enzyme-linked immunosorbent assay (ELISA) (51 patients vs. 86 controls) and postmortem brain MIF levels with a western blotting assay (18 patients vs. 22 controls). Subsequently, we genotyped the MIF-794CATT microsatellite with a fluorescence-based fragment assay and the MIF-173G/C SNP with a TaqMan SNP genotyping assay (1483 patients vs. 1454 controls). RESULTS:Serum MIF levels were significantly higher in patients with schizophrenia than in controls (p=0.00118), and were positively correlated with antipsychotic dose (Spearman's r=0.222, p=0.0402). In addition, an earlier age of onset was observed in patients with a high serum MIF level (≥40ng/mL) than those with a low serum MIF level (<40ng/mL) (p=0.0392). However, postmortem brain MIF levels did not differ between patients with schizophrenia and controls. The association study revealed that the CATT-G haplotype was nominally significantly associated with schizophrenia (p=0.0338), and that the CATT allele and CATT-G haplotype were significantly associated with female adolescent-onset schizophrenia (AsOS) (corrected p=0.0222 and p=0.0147, respectively). CONCLUSIONS:These results suggest that serum MIF level is a potential pharmacodynamic and/or monitoring marker of schizophrenia, and is related to a novel antipsychotic effect beyond dopamine antagonism. Furthermore, the MIF gene polymorphisms are associated with the risk for schizophrenia especially in adolescent females, and are potential stratification markers of schizophrenia. Further studies of MIF are warranted to elucidate the pathophysiology of schizophrenia and the effects of antipsychotics.
Macrophage migration inhibitory factor promoter polymorphisms are associated with disease activity in rheumatoid arthritis patients from Southern Mexico.
Santoscoy-Ascencio Guillermo,Baños-Hernández Christian Johana,Navarro-Zarza José Eduardo,Hernández-Bello Jorge,Bucala Richard,López-Quintero Andres,Valdés-Alvarado Emmanuel,Parra-Rojas Isela,Illades-Aguiar Berenice,Muñoz-Valle José Francisco
Molecular genetics & genomic medicine
BACKGROUND:Macrophage migration inhibitory factor (MIF) is a cytokine capable of stimulating inflammatory cytokine and matrix metalloproteinase production from macrophages and synovial fibroblasts, which leads to persistent inflammation and bone degradation, two of the major pathological processes in rheumatoid arthritis (RA). The aim of this study was to evaluate the association of MIF promoter polymorphisms (-794CATT rs5844572 and -173G > C, rs755622), circulating MIF levels, and mRNA expression with RA susceptibility and disease activity. METHODS:A case-control study was conducted in 200 RA patients and 200 control subjects (CS) from Southern Mexico. Genotyping was performed by conventional PCR and PCR-RFLP methods. MIF mRNA expression was quantified by real-time PCR and MIF serum levels were determined by an ELISA kit. RESULTS:The 7,7 (-794CATT ) and -173CC (-173G > C) genotypes were associated with higher disease activity in RA patients. MIF serum levels were increased, and MIF mRNA expression was reduced in RA patients as compared to CS. In addition, RA patients with moderate disease activity had higher MIF levels than those with low disease activity. The -794CATT and -173G > C MIF polymorphisms were not associated with RA susceptibility. CONCLUSION:These results suggest an important role of MIF polymorphisms and MIF serum levels with disease activity in RA.
Role of macrophage migration inhibitory factor (MIF) in the skin.
Journal of dermatological science
Macrophage migration inhibitory factor (MIF) functions as a pleiotropic protein, participating in both inflammation and immune responses. MIF was originally discovered as a lymphokine involved in delayed type hypersensitivity and various macrophage functions, including phagocytosis, and tumor surveillance. Recently, MIF has been re-evaluated as a pro-inflammatory cytokine and identified as a pituitary-derived hormone, potentiating endotoxemia. MIF is ubiquitously expressed in various tissues, including the skin. Clinical evidence of increased MIF expression in inflammatory diseases supports this potential role of MIF in inflammation. In addition to its role in inflammation, MIF has been shown to exhibit growth-promoting activity, with anti-MIF antibodies effectively suppressing tumor growth and tumor-associated angiogenesis. This review presents the latest findings on the roles of MIF in the skin with regard to inflammation, the immune response, skin disease, tumorigenesis and cutaneous wound healing, and discusses its potential functions in various pathophysiological states.
The diagnostic value of macrophage migration inhibitory factor (MIF) in gastric cancer.
Camlica Hakan,Duranyildiz Derya,Oguz Hilal,Oral Ethem Nezih,Yasasever Vildan
Pathology oncology research : POR
The present study was conducted to investigate the sensitivity, specificity, predictive values and accuracy of serum MIF, CEA, CA 19-9 levels and their various combinations in patients with gastric cancer. Study group consists of pathologically verified, gastric cancer (n = 63) and apparently healthy controls (n = 50). Serum MIF concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Serum values of patients were significantly higher than the controls (p = 0.011). Diagnostic sensitivity and specificity, predictive values and accuracies were calculated for each marker and their various combinations. The best results were achieved with the marker combination of MIF-CEA-CA 19-9 and MIF-CEA combination. In our opinion, the combination of the markers MIF-CEA is a valuable diagnostic tool for gastric cancer.
Macrophage migration inhibitory factor (MIF) in the stratum corneum: a marker of the local severity of atopic dermatitis.
Yasuda Chie,Enomoto Akiko,Ishiwatari Shioji,Mori Naoya,Kagoyama Ko,Matsunaga Kenji,Yoshihisa Yoko,Matsukuma Shoko,Shimizu Tadamichi
Different biomarkers are used to evaluate the severity of atopic dermatitis (AD); however, it remains difficult to determine the severity of localized skin lesions. MIF plays an essential role in the pathophysiology of skin inflammation. To establish whether the MIF level in the stratum corneum (SC) serves as a marker of the severity of AD lesions, we examined the SC MIF (scMIF) levels in AD patients. The SC of the cheek, neck and upper arm skin was collected using tape stripping, and the scMIF levels were measured. Consequently, the scMIF levels were found to be significantly higher in the involved skin lesions than the uninvolved areas within the same patient. Moreover, the scMIF levels were significantly correlated with the severity of local skin lesions. These findings suggest that the scMIF level can be used as an effective marker for evaluating the local severity of AD.
Association of MIF in serum and synovial fluid with severity of knee osteoarthritis.
Liu Minghui,Hu Chunhe
OBJECTIVE:Recent evidences suggest that inflammation contributes to the development and progression of osteoarthritis (OA). This study aims to determine macrophage migration inhibitory factor (MIF) levels in serum and synovial fluid (SF) of patients with knee OA and to analyze the association of MIF levels with the radiographic severity of OA. DESIGN AND METHODS:224 patients with knee OA and 186 healthy controls were enrolled in this study. RESULTS:Higher levels of serum MIF were found in knee OA patients compared with healthy controls. Knee OA patients with Kellgren and Lawrence (KL) grade 4 showed significantly elevated MIF levels in serum and SF compared with those with KL grade 2 and 3. MIF levels in serum and SF of knee OA patients were significantly related to disease severity evaluated by KL grading criteria. CONCLUSION:MIF levels in serum and SF were closely related to the radiographic severity of OA.
Increased macrophage migration inhibitory factor (MIF) plasma levels in acute HIV-1 infection.
Delaloye Julie,De Bruin Irma J A,Darling Katharine E A,Reymond Marlies Knaup,Sweep Fred C G J,Roger Thierry,Calandra Thierry,Cavassini Matthias
Considering macrophage migratory inhibitory factor (MIF) as a critical pro-inflammatory cytokine of the immune system, we evaluated plasma MIF levels in 89 HIV-infected adults. Plasma MIF levels were higher in HIV-infected than in HIV-negative individuals. Highest MIF levels were observed during acute HIV infection (AHI) whilst patients on antiretroviral therapy (ART) had lower MIF levels, regardless of ART efficacy. Our results suggest that MIF is an integral component of the cytokine storm characteristic of AHI.
Macrophage migration inhibitory factor (MIF) promoter polymorphisms (-794 CATT5-8 and -173 G>C): association with MIF and TNFα in psoriatic arthritis.
Morales-Zambrano Ramsés,Bautista-Herrera Luis A,De la Cruz-Mosso Ulises,Villanueva-Quintero Guadalupe D,Padilla-Gutiérrez Jorge R,Valle Yeminia,Parra-Rojas Isela,Rangel-Villalobos Héctor,Gutiérrez-Ureña Sergio R,Muñoz-Valle José F
International journal of clinical and experimental medicine
Psoriatic arthritis (PsA) is an autoimmune disease with a complex interaction of gene and with a dysregulation of pro-inflammatory cytokine such as Macrophage migration Inhibitory Factor (MIF) and Tumor Necrosis Factor-alpha (TNFα). Two polymorphisms identified in the promoter region of the MIF gene have been described: the STR-794 CATT5-8 (rs5844572) and the SNP-173 G>C (rs755622), which are associated with increased MIF levels in circulation and with autoimmune diseases in several populations. In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with PsA susceptibility and clinical variables as well as with MIF and TNFα serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 and -173 G>C MIF polymorphisms was performed by PCR and PCR-RFLP respectively in 50 PsA patients and 100 healthy subjects (HS). MIF and TNFα serum levels were determined by ELISA. A significant increase of MIF (PsA: 7.8 vs. HS: 5.25 ng/mL; p < 0.001) and TNFα (PsA: 24.6 vs. HS: 9.9 pg/mL; p < 0.001) levels was found in PsA patients, a significant correlation was observed between MIF and TNFα (r = 0.41; p < 0.01). The 5,6 repeats genotype of the -794 CATT5-8 MIF was associated with protection to PsA (OR = 0.29; CI 0.77-0.98; p = 0.03), and the G/C genotype (OR = 7.5; CI 2.92-21.64; p < 0.001) and the -173*C allele (OR = 2.45; CI 1.43-4.20; p < 0.001) of the -173 G>C MIF were associated with susceptibility to PsA. In conclusion the -173*C allele is associated with susceptibility to PsA in Mexican-Mestizo population, whereas the correlation between MIF and TNFα soluble levels provided evidence that both cytokines are closely related in the pathophysiology of the PsA.
Serum levels of macrophage migration-inhibitory factor (MIF) have diagnostic, predictive and prognostic roles in epithelial ovarian cancer patients.
Tas Faruk,Karabulut Senem,Serilmez Murat,Ciftci Rumeysa,Duranyildiz Derya
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
Macrophage migration-inhibitory factor (MIF) plays an important role in the pathogenesis of multiple malignancies, and its expression strongly also affects outcomes of cancer patients. The objective of this study was to determine the clinical significance of serum levels of MIF in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were enrolled into this study. Serum MIF concentrations were determined using the solid-phase sandwich ELISA method. Age- and sex-matched 30 healthy controls were included in the analysis. Median age of patients was 56.5 years old, range 22 to 83 years. Majority of the patients had an advanced disease (International Federation of Gynecologists and Obstetricians (FIGO) stages III and IV) (90%). Baseline serum MIF levels were significantly higher than those in the healthy control group (p = 0.005). No known clinical variables including histology, grade of histology, stage of disease, debulking surgery, and serum CA 125 levels were found to be correlated with serum MIF levels (p > 0.05). Only those chemotherapy-unresponsive patients had higher serum MIF levels compared with responsive ones (p = 0.02). Patients with elevated serum MIF concentrations had significantly unfavorable overall survival compared to those with lower levels (p = 0.01). However, a serum MIF level was found to play no prognostic role for progression-free survival (p = 0.09). In conclusion, serum levels of MIF have diagnostic, predictive, and prognostic roles in EOC patients.
Evaluation of macrophage migration inhibitory factor (MIF) levels in serum and lesional skin of patients with alopecia areata.
Salem Samar A,Asaad Marwa K,Elsayed Sherin B,Sehsah Hend M
International journal of dermatology
BACKGROUND:Alopecia areata (AA) is a non-scarring hair loss condition, the pathogenesis of which is not fully understood. Genetic predisposition, autoimmunity, and stress may each play a role. Macrophage migration inhibitory factor (MIF) is a cytokine that plays a role in the regulation of macrophage function. It also initiates inflammation and immune response by regulating a number of proinflammatory cytokines. OBJECTIVES:This study was designed to study serum and lesional skin biopsy MIF levels in AA patients and to assess their associations with disease severity. METHODS:This study included 30 patients with AA and 15 age- and sex-matched healthy control subjects. Quantitative measurements of MIF concentrations in sera and skin samples were obtained in both patients and control subjects. Associations with disease severity (assessed using the Severity of Alopecia Tool) were evaluated. RESULTS:Mean ± standard deviation (SD) MIF levels in serum and skin were significantly higher in AA patients (45.03 ± 26.98 ng/ml and 73.83 ± 29.81 ng/ml, respectively) than in controls (7.73 ± 1.62 ng/ml and 0.40 ± 1.12 ng/ml, respectively) (P < 0.01). Mean ± SD serum and skin MIF levels were also found to be higher in severe AA (69.93 ± 11.51 ng/ml and 100.80 ± 13.77 ng/ml, respectively) than in mild AA (20.13 ± 6.84 ng/ml and 46.87 ± 9.65 ng/ml, respectively) (P < 0.01). CONCLUSIONS:The finding that MIF is increased in serum and lesional skin of AA patients indicates its possible involvement in the pathogenesis of the disease.
Haplotypes of (-794(CATT)/-173G>C) gene polymorphisms and its soluble levels in basal cell carcinoma in western Mexican population.
Guevara-Gutiérrez Elizabeth,Castro-Jonguitud María José,De la Torre-Flores Susana Elizabeth,Muñoz-Valle José Francisco,Tlacuilo-Parra Alberto,Salazar-Torres Francisco Javier,Valle Yeminia,Padilla-Gutiérrez Jorge Ramón,Martínez-Fernández Diana Emilia,Valdés-Alvarado Emmanuel
Journal of investigative medicine : the official publication of the American Federation for Clinical Research
Basal cell carcinoma (BCC) is the most common dermatological neoplasms in Caucasian populations. In Mexico, a prevalence of 3.9 per 1000 habitants is estimated. Recently, the macrophage migration inhibitory factor (MIF) has been related to different types of cancer. Therefore, this study aimed to investigate the genetic association of haplotypes of [-794(CATT)5-8/-173G>C]MIF gene polymorphisms and its soluble levels in BCC. A total of 360 individuals were recruited for the study, that is, 180 of the total amounts were patients with BCC histologically confirmed and the remaining 180 individuals were identified as control subjects (CS). Both polymorphisms were genotyped by PCR and PCR-RFLP (restriction fragment length polymorphism), and MIF serum levels were measured by ELISA kit. A borderline difference was found between the 55 genotype and the susceptibility to BCC (5.6% vs 1.7% in BCC and CS, respectively, OR=3.7 and p=0.04). Furthermore, the haplotype 7G showed a significant association with BCC (p=0.02, OR=1.99). Concerning MIF soluble levels, patients with BCC showed a media of 2.1 ng/mL and CS showed 4.4 ng/mL, the comparison between groups was significant (p<0.01). Our findings suggest that the 55 genotype and the haplotype 7G are associated with the susceptibility to BCC; furthermore, a significant difference was found between MIF soluble levels in both study groups.
Macrophage migration inhibitory factor promoter polymorphisms (-794 CATT5-8): Relationship with soluble MIF levels in coronary atherosclerotic disease subjects.
Qian Lu,Wang Xiao-Yan,Thapa Saroj,Tao Lu-Yuan,Wu Shao-Ze,Luo Gao-Jiang,Wang Lu-Ping,Wang Jiao-Ni,Wang Jie,Li Ji,Tang Ji-Fei,Ji Kang-Ting
BMC cardiovascular disorders
BACKGROUND:We analyzed the relationship of -794 CATT5-8 MIF polymorphisms with soluble MIF in Coronary Atherosclerotic Disease (CAD) patients. METHODS:A total of 256 patients selected, on which 186 normal-coronary and 70 Coronary artery disease subjects, were recruited in the study (Retrospectively registered). Genotyping of -794 CATT5-8 polymorphisms were performed by PCR and DNA sequencing. Serum MIF levels were measured using an ELISA kit. Patients were classified by coronary angiogram, and CAD based on Gensini's integral degree (angiographic scoring system). RESULTS:The allele frequency and genotype frequency of -794 CATT5-8 did not show any differences in normal-coronary subjects and CAD subjects. In CAD patients, serum MIF levels was lower in CATT (5) subjects than in CATT (7) subjects, while the genotype of -794 CATT5-8 did not show differences in serum MIF levels. In addition, we found a decrease in serum MIF levels in carriers of the (5/5) genotypes the -794 CATT5-8 MIF polymorphisms, although it was not significant. There was no relationship of CAD class and the allele frequency of -794 CATT5-8. CONCLUSIONS:This study found no association between CAD class and -794 CATT5-8 MIF polymorphisms with soluble MIF levels in CAD Subjects. TRIAL REGISTRATION:NCT01750502 (November 2012, Retrospectively registered).
[Macrophage migration inhibitory factor (MIF) gene -173 G>C polymorphism and its relationship to coronary artery disease and type 2 diabetes].
Çoban Neslihan,Erkan Aycan Fahri,Ekici Berkay,Kaşit Maide,Erginel Ünaltuna Nihan,Vurgun Eren
Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir
OBJECTIVE:Recent studies indicate that macrophage migration inhibitory factor (MIF) is a potent proinflammatory cytokine which mediates the inflammatory process during atherosclerosis. The purpose of the study was to investigate an association between MIF gene polymorphism and type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) in the Turkish population. METHODS:A total of 139 unselected Turkish patients with significant CAD (coronary lesion with 50-100% stenosis) and 120 control participants (coronary lesion with <30% stenosis) were genotyped for MIF rs755622 polymorphisms using hybridization probes in a Roche LightCycler 480 Real-Time Polymerase Chain Reaction 480 device. Blood samples were drawn before coronary angiography. Gensini and SYNTAX scores were used to determine the angiographic extent and severity of CAD. RESULTS:When the groups were stratified according to T2DM, polymorphism of MIF was not associated with T2DM in CAD patients (p>0.05). In the same subgroups, carriers of the MIF common allele in the control group demonstrated a protection against developing T2DM compared with noncarriers (p<0.05). In addition, MIF C allele carriage was associated with higher glycated hemoglobin (HbA1c) in the T2DM group (p=0.038). CONCLUSION:The MIF rs755622 polymorphism was associated with HbA1c. This result suggests that the MIF gene variant may contribute to CAD risk through diabetes in the Turkish population.
Macrophage migration inhibitory factor polymorphisms are a potential susceptibility marker in systemic sclerosis from southern Mexican population: association with MIF mRNA expression and cytokine profile.
Baños-Hernández Christian Johana,Navarro-Zarza José Eduardo,Bucala Richard,Hernández-Bello Jorge,Parra-Rojas Isela,Ramírez-Dueñas María Guadalupe,García-Arellano Samuel,Hernández-Palma Luis Alexis,Machado-Sulbarán Andrea Carolina,Muñoz-Valle José Francisco
INTRODUCTION:Systemic sclerosis (SSc) is a complex autoimmune disease, characterized by microvascular lesions, autoimmunity, and fibrosis. It is suggested that MIF participates in the amplification of the proinflammatory process in SSc; moreover, the promoter polymorphisms - 794 CATT (rs5844572) and - 173G>C (rs755622) in the MIF gene have been associated with an increase in MIF serum levels in several autoimmune diseases. The aim of this study was to analyze the relationship of the - 794 CATT and - 173G>C MIF polymorphisms with mRNA expression, MIF serum levels, and the Th1/Th2/Th17 cytokine profile in SSc. MATERIALS AND METHODS:A case-control study was carried out that included 50 patients with SSc and 100 control subjects (CS). Both polymorphisms were genotyped by PCR and PCR-RFLP. MIF levels were measured by ELISA kit. The cytokine profile and the MIF mRNA expression were quantified by BioPlex MagPix system and real-time PCR, respectively. RESULTS:An association between the - 794 CATT and - 173*C MIF alleles and the 7C haplotype with SSc susceptibility was found (p < 0.05). Also, the 7C haplotype was associated with increased MIF mRNA expression (p = 0.03) in SSc. In addition, an increase of IL-1β and IL-6 serum levels in SSc patients was found as well as a positive correlation between MIF serum levels and Th1 and Th17 cytokine profiles. CONCLUSION:The MIF 7C haplotype is a susceptibility marker for SSc in the southern Mexican population and is associated with MIF mRNA expression. Moreover, there is a positive correlation between MIF serum levels and Th1 and Th17 inflammatory response in SSc.
Macrophage migration inhibitory factor is differentially expressed in normal and choriocarcinoma trophoblast cells.
Vilotic A,Bojic-Trbojevic Z,Vicovac L,Jovanovic Krivokuca M
Trophoblast cells are specific for placenta, the organ necessary for development of the fetus. Trophoblast derived choriocarcinoma is a rare cancer, with high metastatic potential, invading surrounding tissues and distant organs. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine involved in a wide range of biological processes, which is increased in almost all human cancers. Expression of MIF in normal and choriocarcinoma trophoblast cells is investigated here, using normal extravillous trophoblast derived cell line HTR-8/SVneo, and choriocarcinoma cell lines JAR and JEG3. Expression of MIF and its receptors CD74 and CXCR2 was investigated at mRNA level using qPCR. Expression of MIF protein was studied using immunofluorescence and western blot, under reducing and native conditions, in whole cell lysates, subcellular fractions and conditioned media. The expression of MIF mRNA was similar in all three cell lines, while CD74 mRNA was more expressed in choriocarcinoma cells (14-fold for JAR, 12-fold for JEG3, p<0.01). CXCR2 mRNA was higher in JEG3 cell line compared to HTR-8/SVneo cells (6-fold, p<0.01). While the cellular level of MIF was similar, the level of secreted MIF was lower in JAR cell conditioned media compared to media of both HTR-8/SVneo (2.8-fold, p<0.01) and JEG3 cells (4.1-fold, p<0.001). Cellular distribution of MIF was similar between the studied cell types. MIF was predominantly cytoplasmic, but also detected in membrane, nuclear soluble and nuclear chromatin fraction. MIF appeared in high molecular weight complexes of >150 kDa under native conditions. A band of 140-145 kDa was consistently present in JEG3 cell lysates, while it was absent or very weak in other cell types. These results show that MIF/CD74 axis is shifted in choriocarcinoma, as previously shown for other cancers, and further justifies research towards the most effective MIF targeting therapeutics.
Dendritic cell subsets and immunological milieu in inflammatory human papilloma virus-related skin lesions.
Nakayama Yumi,Asagoe Kenji,Yamauchi Akiko,Yamamoto Takenobu,Shirafuji Yoshinori,Morizane Shin,Nakanishi Gen,Iwatsuki Keiji
Journal of dermatological science
BACKGROUND:Human papilloma virus (HPV)-related warts persist, evading host immune surveillance, but sometimes disappear with inflammation. OBJECTIVES:To elucidate the immune evasion mechanisms of HPV, we have examined the density, dynamics, and subsets of dendritic cell (DC) types in non-inflammatory or inflammatory HPV-related skin lesions such as warts and Bowen's disease (HPV-Bowen), and compared the epidermal expression levels of macrophage inflammatory protein (MIP)-3α and E-cadherin. METHODS:The expression of various DC markers, MIP-3α, and E-cadherin in the tissue samples obtained from patients with warts, HPV-Bowen and HPV-unrelated skin diseases was evaluated by immunohistochemistry. MIP-3α gene expression levels were examined in warts and HPV-Bowen by in situ hybridization (ISH) and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS:The numbers of Langerhans cells (LCs) and the expression levels of MIP-3α and E-cadherin were decreased in non-inflammatory warts and HPV-Bowen, as compared with normal skin. Both epidermal LCs and MIP-3α expression reappeared in inflammatory warts, associated with dermal infiltrates composed of many cytotoxic T cells and various subsets of DCs, while cellular infiltrates in HPV-Bowen contained many B cells and plasma cells with sparse infiltration of DCs. The upregulation of MIP-3α gene expression was confirmed in the inflammatory warts and HPV-Bowen by ISH and RT-qPCR. CONCLUSIONS:The depletion of LCs in the non-inflammatory warts and HPV-Bowen is associated with a down-regulation of expression levels of MIP-3α and E-cadherin in the lesional keratinocytes. MIP-3α expression is upregulated in lesional keratinocytes of inflammatory warts, with the subsequent recruitment of various DC subsets and cytotoxic T cells, whereas plasma cell-rich infiltration was induced in HPV-Bowen.
Association of TLR2 and TLR4 gene polymorphism with susceptibility to wart infections and their response to candida antigen immunotherapy.
Tantawy Enas A,El-Beyali Abdallah A,Gohar Maha K,Ibrahim Zynab S,Nasr Mohamed,Marei Ayman
The Journal of dermatological treatment
Warts are prevalent human papilloma virus (HPV) infections which can cause physical and psychological problems. Candida antigen immunotherapy is a safe and promising treatment of warts. Toll-like receptors (TLRs) 2 and 4 gene polymorphisms are implicated in susceptibility and progression of several diseases. To assess the role of TLR2Arg753GLN and TLR4Asp299Gly polymorphisms in susceptibility to HPV wart infections and their possible effect on response to Candida antigen immunotherapy. A total of 78 patients and 78 healthy subjects were enrolled in this case control study. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to detect TLR2Arg753GLN and TLR4Asp299Gly genes polymorphisms. Patients' lesions were injected with Candida antigens and the response was assessed. The mutant AA and GG genotypes of TLR2Arg753GLN and TLR4Asp299Gly were significantly detected in patients than controls ( < .001 and = .01, respectively). Intralesional Candida antigen injections achieved complete and partial clearance in 62.8 and 20.5% of lesions, respectively. No association was found between the studied polymorphisms and response to Candida antigen injections. TLR2Arg753GLN and TLR4Asp299Gly polymorphisms are associated with susceptibility to wart infections, but with no effect on their response to Candida immunotherapy.
Role of MIF/CD74 signaling pathway in the development of pleural mesothelioma.
D'Amato-Brito Cintia,Cipriano Davide,Colin Didier J,Germain Stéphane,Seimbille Yann,Robert John H,Triponez Frédéric,Serre-Beinier Véronique
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine implicated in acute and chronic inflammatory diseases. MIF is overexpressed in various tumors. It displays a number of functions that provide a direct link between the process of inflammation and tumor growth. Our group recently identified the MIF-receptor CD74 as an independent prognostic factor for overall survival in patients with malignant pleural mesothelioma.In the present study, we compared the levels of expression of MIF and CD74 in different human mesothelioma cell lines and investigated their physiopathological functions in vitro and in vivo.Human mesothelioma cells expressed more CD74 and secreted less MIF than non tumoral MeT5A cells, suggesting a higher sensitivity to MIF. In mesothelioma cells, high MIF levels were associated with a high multiplication rate of cells. In vitro, reduction of MIF or CD74 levels in both mesothelioma cell lines showed that the MIF/CD74 signaling pathway promoted tumor cell proliferation and protected MPM cells from apoptosis. Finally, mesothelioma cell lines expressing high CD74 levels had a low tumorigenic potential after xenogeneic implantation in athymic nude mice.All these data highlight the complexity of the MIF/CD74 signaling pathway in the development of mesothelioma.
Macrophage Migration Inhibitory Factor (MIF): A Glucocorticoid Counter-Regulator within the Immune System.
Calandra Thierry,Bucala Richard
Critical reviews in immunology
Originally described as a T lymphocyte-derived factor that inhibited the random migration of macrophages, the protein known as macrophage migration inhibitory factor (MIF) was an enigmatic cytokine for almost 3 decades. In recent years, the discovery of MIF as a product of the anterior pituitary gland and the cloning and expression of bioactive, recombinant MIF protein have led to the definition of its critical biological role in vivo. MIF has the unique property of being released from macrophages and T lymphocytes that have been stimulated by glucocorticoids. Once released, MIF overcomes the inhibitory effects of glucocorticoids on TNFα, IL-1β, IL-6, and IL-8 production by LPS-stimulated monocytes in vitro and suppresses the protective effects of steroids against lethal endotoxemia in vivo. MIF also antagonizes glucocorticoid inhibition of T-cell proliferation in vitro by restoring IL-2 and IFN-γ production. This observation has identified a pivotal role for MIF within the immune system and fills an important gap in our understanding of the control of inflammatory and immune responses. Glucocorticoids have long been considered to be an integral component of the stress response to infection or tissue invasion and serve to modulate inflammatory and immune responses. MIF is the first mediator to be identified that can counter-regulate the inhibitory effects of glucocorticoids and thus plays a critical role in the host control of inflammation and immunity.
Serum Levels of Migration Inhibitory Factor (MIF) and Expression of MIF and Its Receptor CD74 in Lepromatous Leprosy Patients: A Preliminary Report.
Martinez-Guzman Marco Alonso,Alvarado-Navarro Anabell,Delgado-Rizo Vidal,Garcia-Orozco Alejandra,Mayorga-Rodríguez Jorge Arturo,Pereira-Suarez Ana Laura,Fafutis-Morris Mary
Frontiers in immunology
Leprosy is a chronic disease caused by that affects the skin and peripheral nerves. It may present as one of two distinct poles: the self-limiting tuberculoid leprosy and the highly infectious lepromatous leprosy (LL) characterized by -specific absence of cellular immune response. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) enhance the bactericide activities of macrophages after interaction with its receptor, CD74. Importantly, MIF also possesses chemoattractant properties, and it is a key factor for the activation of macrophages and in blood to promote leukocytes migration. MIF-mediated activation of macrophages is a key process for the elimination of pathogens such as ; however, its participation for the clearance of is unclear. The aim of this study was to evaluate the serum levels of MIF as well as MIF and CD74 expression in skin lesions of LL and compare it with healthy skin (HSk) taken from subjects attending to dermatological consult. Samples of serum and skin biopsies were taken from 39 LL patients and compared with 36 serum samples of healthy subjects (HS) and 10 biopsies of HSk. Serum samples were analyzed by ELISA and skin biopsies by immunohistochemistry (IHC). IHC smears were observed in 12 100× microscopic fields, in which percentage of stained cells and staining intensity were evaluated. Both variables were used to calculate a semi-quantitative expression score that ranged from 0 to 3+. We found no differences in MIF levels between LL patients and HS in sera. In addition, MIF was observed in over 75% of cells with high intensity in the skin of patients and HSk. Although we found no differences in MIF expression between the groups, a CD74 score statistically higher was found in LL skin than HSk ( < 0.001); this was the result of a higher percentage of cells positive for CD74 ( < 0.001). As a conclusion, we found that CD74-positive cells are intensely recruited to the skin with LL lesions. In this manner, MIF signaling may be enhanced in the skin of LL patients due to increased expression of its receptor, but further studies are required.
A novel gene-wide haplotype at the macrophage migration inhibitory factor (MIF) locus is associated with endometrioma.
Chekini Zahra,Poursadoughian Yaran Atiyeh,Ansari-Pour Naser,Shahhoseini Maryam,Ramazanali Fariba,Aflatoonian Reza,Afsharian Parvaneh
European journal of obstetrics, gynecology, and reproductive biology
OBJECTIVE:Endometriosis is a common complex gynecological disorder that may result in infertility. Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine that is overexpressed in endometriosis tissues. However, hitherto, no study tested the possible relevancy at genetic level. The aim of this study was to evaluate MIF polymorphisms and possible associations between haplotype of the gene and endometrioma. STUDY DESIGN:In this experiment, 115 patients with confirmed endometrioma and 120 of women who were not diagnosed with endometrioma were recruited for this case-control genetic association study. The coding region of MIF was resequenced to detect variations of potential significance. Restriction fragment length polymorphism was used to type the -173 G/C (rs755622) promoter Single nucleotide polymorphism (SNP). Haplotype analyses were then undertaken to assess the effect of genetic variations. RESULTS:We detected one functional SNP in promoter (rs755622) and non-functional mutations across the gene including (rs2096525, rs182012324, rs33958703 and rs2070766) in our samples. However, haplotype analysis showed a significant association between MIF and endometrioma where a single haplotype CC carrying only the minor allele at -173 G/C was significantly over-represented in the patients group (P = 0.007) and remained significant even after correction for (Bonferroni adjusted P = 0.028). CONCLUSION:We report a strong linkage between a novel MIF haplotype and endometrioma. This association is consistent with expression data at both transcript and protein levels suggesting the -173C/G promoter as a critical factor.
Associations between circulating macrophage migration inhibitory factor (MIF) levels and rheumatoid arthritis, and between gene polymorphisms and disease susceptibility: a meta-analysis.
Bae Sang-Cheol,Lee Young Ho
Postgraduate medical journal
AIM:To systematically review evidence regarding the relationship between circulating macrophage migration inhibitory factor (MIF) levels and rheumatoid arthritis (RA), and the association between gene polymorphisms and RA susceptibility. DESIGN:We performed a meta-analysis on data of serum/plasma MIF levels in patients with RA and in controls, and on associations between the -173 C/G and -794CATT polymorphisms and RA susceptibility. PATIENTS:Twelve studies, comprising a total of 362 RA cases and 531 controls evaluated for MIF levels, and 2367 RA cases and 2395 controls evaluated for polymorphisms, were included. RESULTS:MIF levels were significantly higher in the RA group than in the control group (standardised mean difference (95% CI) 0.923 (0.766 to 1.080), p<0.001). Stratification by ethnicity revealed significantly higher MIF levels in the RA group in Caucasian, Asian and Latin American populations. MIF levels were significantly higher in patients with RA, regardless of adjustment, sample size or data type evaluated. RA was identified to be significantly associated with the -173 C allele (OR (95% CI) 1.271 (1.141 to 1.416), p<0.001), as well as with the -794CATT allele (OR (95% CI) 1.229 (1.084 to 1.415), p=0.002) and the -794CATT--173C haplotype RA (OR (95% CI) 1.433 (1.138 to 1.805), p=0.002). CONCLUSIONS:Our meta-analyses revealed significantly higher circulating MIF levels in patients with RA, and found evidence of associations between the -173 C/G and -794CATT polymorphisms and RA susceptibility.
Genotyping Two Promoter Polymorphisms in the MIF Gene: A -794 CATT Microsatellite Repeat and a -173 G/C SNP.
Leng Lin,Siu Edwin,Bucala Richard
Methods in molecular biology (Clifton, N.J.)
Macrophage migration inhibitory factor (MIF) is an upstream proinflammatory cytokine encoded by a functionally polymorphic locus. The promoter region of the human MIF gene contains two polymorphisms. A variable nucleotide tandem repeat at position -794 comprises five to eight CATT repeats (referred to henceforth by numbers from 5 to 8, rs5844572). Gene reporter assays show a proportional increase in transcription with CATT repeat number; the 5-repeat allele leads to low expression, and the 6-, 7-, and 8-repeat alleles lead to correspondingly higher expression of MIF. A second MIF promoter polymorphism comprises a G-to-C single nucleotide polymorphism (SNP) at position -173 (rs755622), which is in strong linkage disequilibrium with -794 7-CATT and is associated with arthritis clinical severity and higher serum and synovial fluid MIF levels. This allele also has been reported to confer improved survival in patients with outpatient pneumonia. In this chapter, we will introduce the methods of genotyping CATT repeats and the MIF -173 G/C from human samples.