Macrophage Migration Inhibitory Factor Gene Research Articles

Macrophage migration inhibitory factor (MIF) gene is associated with adolescents’ cortisol reactivity and anxiety

Emerging evidence points to interactions between inflammatory markers and stress reactivity in predicting mental health risk, but underlying mechanisms are not well understood. Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic cytokine involved in inflammatory signaling and Hypothalamus Pituitary Adrenal (HPA) axis stress-response, and has recently been identified as a candidate biomarker for depression and anxiety risk. We examined polymorphic variations of the MIF gene in association with baseline MIF levels, HPA axis reactivity, and self-reported anxiety responses to a social stressor in 74 adolescents, ages 10–14 years. Genotyping was performed for two polymorphisms, the -794 CATT5-8 tetranucleotide repeat and the -173*G/C single nucleotide polymorphism (SNP). Youth carrying the MIF-173*C and CATT7 alleles displayed attenuated cortisol reactivity when compared with non-carriers. Children with the CATT7-173*C haplotype displayed lower cortisol reactivity to the stressor compared to those without this haplotype. Additionally, the CATT5-173*C and CATT6-173*C haplotypes were associated with lower self-reported anxiety ratings across the stressor. Results extend prior work pointing to the influence of MIF signaling on neuroendocrine response to stress and suggest a potential pathophysiological pathway underlying risk for stress-related physical and mental health disorders. To our knowledge, these are the first data showing associations between the MIF gene, HPA axis reactivity, and anxiety symptoms during adolescence.

Macrophage Migration Inhibitory Factor -173 G/C Polymorphism: A Global Meta-Analysis across the Disease Spectrum.

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 MIF 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 MIF 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], P < 0.01; OR: 0.81 [0.74–0.89], P < 0.0001; and OR: 0.81 [0.76–0.87], P < 0.0001, respectively) and the recessive models (OR: 0.74 [0.57–0.095], P < 0.01; OR: 0.66 [0.48–0.92], P < 0.0154; and OR: 0.70 [0.60–0.82], P < 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], P < 0.0001; OR: 0.77 [0.72–0.83], P < 0.0001; OR: 0.61 [0.44–0.83], P-value: 0.0017, respectively) and overdominant models (OR: 0.85 [0.77–0.94], P < 0.0001; OR: 0.80 [0.75–0.86], P < 0.0001; OR: 0.73 [0.63–0.85], P-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 MIF-173 G/C in diseases in which the relation is clearer and thus assist the search for more plausible applications.

Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia

BackgroundNumerous 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-794CATT5–8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) with schizophrenia. MethodsWe 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-794CATT5–8 microsatellite with a fluorescence-based fragment assay and the MIF-173G/C SNP with a TaqMan SNP genotyping assay (1483 patients vs. 1454 controls). ResultsSerum 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 CATT6-G haplotype was nominally significantly associated with schizophrenia (p=0.0338), and that the CATT6 allele and CATT6-G haplotype were significantly associated with female adolescent-onset schizophrenia (AsOS) (corrected p=0.0222 and p=0.0147, respectively). ConclusionsThese 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 Gene Polymorphisms (MIF-173CC) Genotyping in Patients with Cardiac Dysfunction: Relationship to Diabetes Mellitus

Introduction: Macrophage migration inhibitory factor (MIF) is an important mediator in inflammation and pathogenesis of cardiomyopathy (CMP). We aim to explore any possible association between polymorphisms of MIF genes and CMP in a cohort of Egyptian patients with cardiac dysfunction with or without diabetes mellitus and to investigate the alliance between the identified genotype and their medical features. Patients and methods: This is a case-control study where 57 patients with CMP were consecutively admitted to CCU compared with 98 matched healthy controls. Patients were subjected to careful clinical history and physical examination, ECG, routine investigations, and echocardiography. All participants were analyzed for codon -173 G/C polymorphism in MIF genes by using PCR-RFLP methods. Results: We found higher Frequency of MIF-173 GG genotype in both diabetic and nondiabetic CMP patients compared to controls (p<0.05). However, we did not find any significant difference in the MIF genotyping between the CMP with or without DM. Conclusion: Our results advocate that MIF may have implications for our understanding of the pathophysiology and perturbation in CMP process. We suggested that GG genotype of MIF (-173) gene may be a risk factor for patients with CMP.

Macrophage migration inhibitory factor (MIF) gene -173 G>C polymorphism and its relationship to coronary artery disease and type 2 diabetes

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. 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. 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). 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.

Association of macrophage migration inhibitory factor - 173 G/C polymorphism with dilated cardiomyopathy in children

Objective The objective of this study was to detect the relation between macrophage migration inhibitory factor (MIF) −173 G/C gene polymorphism and dilated cardiomyopathy (DCM) in children. Background DCM is the most common cardiomyopathy. Myocardial inflammation is one of the commonest mechanisms in cardiomyopathy. MIF plays an important role in the control of innate immune responses and promotes proinflammatory biological activities; hence, MIF gene polymorphisms may predispose affected hosts to severe inflammatory or infectious disease. Patients and methods This study was conducted on 50 patients, 30 patients with DCM and 20 age-matched and sex-matched healthy controls. All patients were subjected to history taking, clinical examination, echocardiography, and laboratory measurement of serum sodium and uric acid. Patients and controls were subjected to PCR-restriction fragment length polymorphism to determine MIF 173 G/C polymorphism. Results Our study revealed a significant statistical difference in the distribution of the genotypes and allele frequencies between patients and controls. Studying the relation between different genotypes and echocardiographic parameters (ejection fraction, fractional shortening, left ventricular end-diastolic diameter and left ventricular end-systolic diameter) revealed a highly significant difference between different genotypes among patients. With regard to laboratory characteristics, there was a significantly higher serum sodium level in the CC genotype, while the uric acid level showed no significant difference between different genotypes among patients. Conclusion In our study, we conclude that the CC genotype of MIF gene may be a risk factor for cardiomyopathic patients and that the C allele is associated with severe clinical condition.

CATT polymorphism in MIF gene promoter is closely related to human pulmonary tuberculosis in a southwestern China population.

Macrophage migration inhibitory factor (MIF) is deemed as an immunoregulatory and proinflammatory cytokine related to the progression of tuberculosis. A CATT short tandem repeat (STR) polymorphism at position −794 in the MIF gene promoter region is associated with the susceptibility to tuberculosis (TB). To investigate whether macrophage MIF gene mif CATT variants are associated with susceptibility to retreatment cases of TB and drug-resistant TB prevalence, genotyping of MIF −794 CATT polymorphism and quantifying of serum MIF were performed to associate MIF−794 CATT polymorphism with new patients and retreatment cases. Significant increases in MIF −794 CATT genotypes 7/8 and allele CATT 8 were observed in TB patients. Significant differences in the genotypic frequencies of MIF −794 CATT (5/X + 6/X vs 7/7 + 7/8) were demonstrated upon comparing the total cases and the new cases of TB with the controls. Significant differences in the allelic frequencies of MIF −794 CATT (5 + 6 vs 7 + 8) were observed in the total cases and new cases of TB. No differences in the genotypic frequencies of the MIF −794 CATT (5/X + 6/X vs 7/7 + 7/8) were observed between the retreatment cases and the controls or between the new cases and retreatment cases. In conclusion, the MIF −794 CATT genotypes 7/8 and allele CATT 8 were highly associated with TB; no differences in the genotypic frequencies of the MIF −794 CATT (5/X + 6/X vs 7/7 + 7/8) were observed between the new cases and retreatment cases.

Serum macrophage migration inhibitory factor levels in leprosy patients with erythema nodosum leprosum.

Erythema nodosum leprosum is an immune-mediated complication of leprosy which causes significant morbidity. Biomarkers in the pathogenesis of erythema nodosum leprosum are not yet fully determined. To determine macrophage migration inhibitory factor levels in the sera of leprosy patients with erythema nodosum leprosum and to correlate the same with clinical parameters. This cross-sectional study included 37 consecutive leprosy patients with active erythema nodosum leprosum and 31 age- and sex-matched controls. Detailed clinical history and examination findings were recorded including the severity and frequency of erythema nodosum leprosum. Slit skin smears and histopathologic examination were done in all patients at baseline. Serum macrophage migration inhibitory factor levels were determined using an enzyme-linked immunosorbent assay. Most of our patients were males (78.4%) and suffering from lepromatous leprosy (27, 73%) with a mean initial bacillary index of 3.38 ± 1.36. Recurrent and chronic patterns of erythema nodosum leprosum were seen in 15 (40.5%) and 6 (16.3%) patients, respectively. Most (86.5%) of our patients presented with moderate to severe erythema nodosum leprosum. The mean serum macrophage migration inhibitory factor level was 21.86 ± 18.7 ng/ml among patients while it was 11.78 ± 8.4 ng/ml in the control group (P < 0.01). There were no statistically significant correlations of macrophage migration inhibitory factor levels with erythema nodosum leprosum frequency or severity. Serum macrophage migration inhibitory factor levels in leprosy patients with no erythema nodosum leprosum and in patients with other inflammatory and autoimmune conditions were not assessed. Hence, this study falls short of providing the predictive value and specificity of higher macrophage migration inhibitory factor concentrations in serum as a biomarker of erythema nodosum leprosum. Macrophage migration inhibitory factor levels are elevated in erythema nodosum leprosum patients as compared to controls. A larger sample size and macrophage migration inhibitory factor gene polymorphism analysis will be needed to elucidate the role of this pro-inflammatory cytokine in erythema nodosum leprosum.

The Expression of Migration Inhibitory Factor mRNA in Peripheral Blood of Children with Systemic Lupus Erythematosus

Aim: This study was aiming at evaluation of the importance and the change in the level of macrophage migration inhibitory factor (MIF) in serum studied by ELISA and in peripheral blood mononuclear cell (PMBC) through the expression of mRNA of MIF studied by reverse PCR and its correlation with disease activity index in patients with systemic lupus erythematosus (SLE). Also, the relationship of MIF with the treatment by corticosteroids and renal involvement was taken into consideration.Material and methods: For this purpose, twenty lupus patients, regularly attending the Pediatric Allergy and Immunology Clinic, Children Hospital, Ain Shams University and fulfilling the American Rheumatism Association Revised Criteria for diagnosis of SLE, were studied in comparison to thirty-five healthy subjects as normal controls. According to the presence or absence of clinical renal involvement, lupus patients were divided into two groups: Group Ia: included 10 patients with clinical renal involvement and Group Ib: comprised 10 patients without clinical renal involvement. Full history taking and clinical examination were done and the SLEDAI was assessed. Also, the following laboratory investigations were performed ESR, routine microscopic urine analysis, 24 hours urine proteins, serum ANA, C3, serum anti-DNA, serum creatinine, serum MIF by ELISA and MIF gene expression through the mRNA in PBMC by rPCR.Results: The results of the present study showed that the MIF in serum and in PBMC were significantly higher among lupus patients as compared to normal controls. In addition, both were significantly higher among lupus patients with clinically evident nephritis than those without. Serum MIF and MIF gene expression were both significantly higher among lupus patients who suffered from symptoms suggestive of lupus nephritis as edema, hematuria, hypertension and positive anti DNA levels than other patients who did not experience these symptoms. In our study, different correlation analysis were done with serum MIF and MIF gene expression and proved to be significantly positive with SLEDAI score, ESR, cumulative dose of steroids, serum creatinine, 24 hour urinary protein and duration of illness in all lupus patients.Conclusions: In conclusion, MIF both in the serum and MIF gene expression by reverse PCR in macrophages were significantly higher in all lupus patients in comparison to healthy controls being significantly higher in those lupus patients with clinically evident nephritis than those without. Also MIF had a significant positive correlation to SLEDAI score and ESR indicating its correlation with disease activity.

Biochemical and structural characterization of a novel cooperative binding mode by Pit-1 with CATT repeats in the macrophage migration inhibitory factor promoter.

Overexpression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) is linked to a number of autoimmune diseases and cancer. MIF production has been correlated to the number of CATT repeats in a microsatellite region upstream of the MIF gene. We have characterized the interaction of pituitary-specific positive transcription factor 1 (Pit-1) with a portion of the MIF promoter region flanking a microsatellite polymorphism (−794 CATT5–8). Using fluorescence anisotropy, we quantified tight complex formation between Pit-1 and an oligonucleotide consisting of eight consecutive CATT repeats (8xCATT) with an apparent Kd of 35 nM. Using competition experiments we found a 23 base pair oligonucleotide with 4xCATT repeats to be the minimum DNA sequence necessary for high affinity interaction with Pit-1. The stoichiometry of the Pit-1 DNA interaction was determined to be 2:1 and binding is cooperative in nature. We subsequently structurally characterized the complex and discovered a completely novel binding mode for Pit-1 in contrast to previously described Pit-1 complex structures. The affinity of Pit-1 for the CATT target sequence was found to be highly dependent on cooperativity. This work lays the groundwork for understanding transcriptional regulation of MIF and pursuing Pit-1 as a therapeutic target to treat MIF-mediated inflammatory disorders.

Expression of macrophage migration inhibitory factor gene in placenta tissue and its correlation with gestational diabetes mellitus

Objective: To investigate the relationship between the expression of macrophage migration inhibitory factor (MIF) gene and the incidence of gestational diabetes mellitus (GDM) in Chinese Han population in northern China. Method: This study was consisted of 126 GDM women and 150 cases of healthy subjects who came from the obstetrics department of Maternity Hospital of Qingdao University and Maternity and Child Care Hospital of Donggang District of Rizhao. The protein expression of MIF in placenta tissue was detected by Western blot method. The blood glucose, insulin levels and other clinical physicochemical index were tested. The differences of MIF, fasting blood-glucose (FBG), fasting insulin (FIN) and the homeostasis model assessment of insulin resistance (HOMA-IR) were compared between the two groups of pregnant women. Result: The level of MIF protein in GDM group (0.85±0.10) was higher than that in healthy pregnant group (0.12±0.09), with significant difference (P<0.001). Insulin resistance index in GDM group were higher than that in healthy pregnant group, with significant difference (P<0.001). Conclusion: The expression of MIF in placental tissues of GDM women was increased and correlated with insulin resistance in GDM patients, suggesting that MIF may play an important role in the occurrence and development of GDM.

A novel macrophage migration inhibitory factor gene from the Pacific white shrimp Litopenaeus vannamei (LvMIF2): comparative sequence and transcription analysis with LvMIF1

Macrophage migration inhibitory factor (MIF) was an ancient cytokine and involved in innate immunity of vertebrates and invertebrates. In the present study, a novel MIF homologue (designated as LvMIF2) has been cloned from the Pacific white shrimp Litopenaeus vannamei via rapid amplification of cDNA ends (RACE) technique. The full-length cDNA sequence of LvMIF2 was 555 bp and contained a 97 bp 5’ untranslated region (UTR) and a 3’ UTR of 110 bp, and an open reading frame (ORF) of 348 bp which coded 115 amino acids. Quantitative realtime PCR (qRT-PCR) analysis indicated that LvMIF2 was constitutively expressed in all the tested tissues, including eyestalk, gill, gonad, heart, hemocytes, hepatopancreas, intestine, muscle, nerve and stomach, with the highest mRNA expression level in hemocytes and hepatopancreas. After Vibrio parahaemolyticus or white spot syndrome virus (WSSV) challenge, the mRNA expression levels of LvMIF2 in hemocytes and hepatopancreas were all sharply upregulated. Comparative sequence and transcription analysis between the previously identified LvMIF1 and LvMIF2 revealed that both LvMIF1 and LvMIF2 might play crucial and functionally differentiated roles in shrimp innate immune responses to bacterial and viral stimulation.

MIF inhibition interferes with the inflammatory and T cell-stimulatory capacity of NOD macrophages and delays autoimmune diabetes onset

Macrophages contribute in the initiation and progression of insulitis during type 1 diabetes (T1D). However, the mechanisms governing their recruitment into the islets as well as the manner of retention and activation are incompletely understood. Here, we investigated a role for macrophage migration inhibitory factor (MIF) and its transmembrane receptor, CD74, in the progression of T1D. Our data indicated elevated MIF concentrations especially in long-standing T1D patients and mice. Additionally, NOD mice featured increased MIF gene expression and CD74+ leukocyte frequencies in the pancreas. We identified F4/80+ macrophages as the main immune cells in the pancreas expressing CD74 and showed that MIF antagonism of NOD macrophages prevented their activation-induced cytokine production. The physiological importance was highlighted by the fact that inhibition of MIF delayed the onset of autoimmune diabetes in two different diabetogenic T cell transfer models. Mechanistically, macrophages pre-conditioned with the MIF inhibitor featured a refractory capacity to trigger T cell activation by keeping them in a naïve state. This study underlines a possible role for MIF/CD74 signaling pathways in promoting macrophage-mediated inflammation in T1D. As therapies directed at the MIF/CD74 pathway are in clinical development, new opportunities may be proposed for arresting T1D progression.

Circulating macrophage migration inhibitory factor levels and its polymorphisms in systemic lupus erythematosus: A meta-analysis.

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 &lt; 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 &lt; 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.

MIF and D-DT are potential disease severity modifiers in male MS subjects

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a -794CATT5-8 microsatellite repeat and a -173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes.

Associations between circulating macrophage migration inhibitory factor (MIF) levels and rheumatoid arthritis, and between MIF gene polymorphisms and disease susceptibility: a meta-analysis

AimTo systematically review evidence regarding the relationship between circulating macrophage migration inhibitory factor (MIF) levels and rheumatoid arthritis (RA), and the association between MIF gene polymorphisms and RA susceptibility.DesignWe performed...

MBL2 and MIF gene polymorphisms in cardiovascular patients with atherosclerotic lesions undergoing heart valve replacement

ABSTRACTThe basic underlying factor for cardiovascular diseases is atherosclerosis, which is a multifactorial disease driven by environmental and genetic factors. We aimed to study the genetic polymorphism in mannose binding lectin-2 (MBL2) and macrophage migration inhibitory factor (MIF) in the arteries of patients with atherosclerotic lesions who underwent cardiac valve replacement for cardiac valve stenosis. Thirty-five patients (38.9 %) operated with coronary bypass surgery (coronary group, CG), 55 (61.1 %) patients operated with aortic or mitral valve replacement (valve group, VG) and 100 healthy controls were analyzed for codon 54 A/B polymorphism in the MBL2 gene and –173 G/C polymorphism in the MIF gene by using the method of polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The comparison of the healthy control group with CG and VG in terms of the MBL2 genotypes revealed significantly lower AA genotype and A allele ratios. The comparison of the healthy control group with CG and VG in terms of the MIF genotypes showed significantly lower GG genotype and G allele ratios. We suggest that the lower frequency of the GG genotype/G allele of the MIF gene and of the AA genotype/A allele of the MBL2 gene may be associated with the ethiopathogenesis of CG and VG patients.

Association of the macrophage migration inhibitory factor promoter polymorphisms with benign lymphoepithelial lesion of lacrimal gland.

To identify the association of the macrophage migration inhibitory factor (MIF) gene polymorphism with the susceptibility of benign lymphoepithelial lesions (BLEL) of the lacrimal gland. A total of 40 BLEL of lacrimal gland cases were matched with 40 healthy subjects (HS). Extraction the plasma and whole blood DNA of patients of lacrimal gland BLEL and HS. Elisa and polymerase chain reaction was used to determine in plasma contents of MIF and MIF gene SNP-173G>C and STR -794 CATT(5-8) polymorphism, respectively. The MIF levels in plasma were significantly higher in patients with lacrimal gland BLEL versus HS (P<0.001). The -173 G>C MIF polymorphism was significantly associated with lacrimal gland BLEL, with a significantly higher frequency of the C allele in lacrimal gland BLEL patients compared with HS (OR=2.38, 95% CI=1.07-5.31, P=0.032), and the -173 C/x is more frequent in patients than in HS, P=0.037. Besides, we found that the carriage rate of the MIF -173C/x is associated with higher plasma levels of MIF in the BLEL of lacrimal gland. MIF -173G/C variants play an insidious role in susceptibility of BLEL of lacrimal gland. Otherwise, there is no statistically significant correlation exists between MIF-794 CATT (5-8) and BLEL of lacrimal gland.

Obacunone causes sustained expression of MKP-1 thus inactivating p38 MAPK to suppress pro-inflammatory mediators through intracellular MIF.

Obacunone (OBA) is a highly oxygenated triterpenoid with various pharmacological activities. In this study, we explored its anti-inflammatory effect and underlying mechanisms in LPS-activated macrophages. Our data showed that OBA potently decreased pro-inflammatory mediators (eg, NO, IL-6, IL-1β, and MCP-1) at the transcriptional and translational levels without cytotoxicity. A mechanism study showed that OBA significantly suppressed p38-mediated AP-1 signaling by stabilizing the mRNA of mitogen-activated protein kinase phosphatase 1 (MKP-1), thus prolonging the expression time of the MKP-1 protein. Next, we used computational target-fishing technology to predict the possible target of OBA. Only one potential target, macrophage migration inhibitory factor (MIF), was presented. Experimentally, the interaction between OBA and MIF was also confirmed. By using an anti-mouse MIF antibody, extracellular MIF (exMIF) was neutralized. Our results showed that autocrine MIF had slight influence on the pro-inflammatory mediator production. Correspondingly, the anti-inflammatory activity of OBA was also not affected. Accordingly, we knocked down the MIF gene in RAW 264.7 cells and obtained stable MIF deficient cells MIF(-), in which the effects of OBA on p38 phosphorylation, AP-1 activation, and pro-inflammatory mediator production in response to LPS nearly disappeared. In contrast to MIF(+) cells, the MKP-1 protein expression time of the MIF(-) cells was markedly prolonged. We conclude that OBA exerts its anti-inflammatory effect by targeting intracellular MIF (inMIF) inhibition to regulate the MKP-1/p38/AP-1 pathway. Our findings also provide a chain of evidence that the inhibition of inMIF, rather than exMIF, may become a novel target for inflammation.

Macrophage Migration Inhibitory Factor (MIF) Gene Promotor Polymorphism Is Associated with Increased Fibrosis in Biliary Atresia Patients, but Not with Disease Susceptibility.

Two polymorphisms, rs755622 and rs5844572, in the promoter region of the macrophage migration inhibitory factor (MIF) gene influence the basal and/or induced transcriptional activity and have been linked to several inflammatory and autoimmune diseases. The aim of this study was to investigate the association between these two polymorphisms and disease susceptibility in patients with biliary atresia (BA). Allele frequencies of rs755622 and rs5844572 were assessed in 60 Egyptian infants with a confirmed diagnosis of BA. DNA was extracted from archival material. For the rs755622, samples were tested using Taqman real-time PCR, and for the rs5844572, samples were tested using fluorescence-based genotyping. The allele frequency in the general population was assessed in 141 healthy adults from the same geographical location. No statistical differences were observed in the allele frequencies of either rs755622 or rs5844572 between BA patients and controls. The homozygous and heterozygous short repeats (5/5, or 5/X) of rs5844572 were observed more frequently (16/28, 57.1%) in BA patients with mild to moderate fibrosis compared with those with marked fibrosis (10/32, 31.3%). The difference was statistically significant (P = 0.032). In conclusion, we observed no association between MIF rs755622 and rs5844572 polymorphisms and susceptibility to BA; however, the rs5844572 could be linked to the rate of progression of the disease and extent of fibrosis.