Modulatory Role of Macrophage Migration Inhibitory Factor on Cytokines and Clinical Features of Sarcoidosis

Background: Sarcoidosis is a systemic granulomatous disease of unknown etiology with a significant heterogeneity in organ manifestations, severity, and clinical course. Subjects with sarcoidosis share several features such as, non-necrotizing granuloma, hypergammaglobulinemia, increased local and circulating inflammatory cytokines, such as interleukin (IL)-6, IL-18, and interferon gamma (IFN-γ). Macrophage migration inhibitory factor (MIF) is a pluripotent chemokine produced by various cell types. The expression of MIF at sites of inflammation suggests a regulatory role in the function of macrophages. The objective of this study was to investigate the role of MIF in the serum and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients in association with clinical features and other cytokines. Methods: Sera and BALs of sarcoidosis patients (n=55) were collected at the time of diagnosis and patients were followed longitudinally for 3 years. Additionally, fifteen healthy controls participated in the study. The medical records of all patients including, demographics, radiography stages, pulmonary function tests, and organ involvements were recorded. The levels of MIF, IL-18, IL-10, IL-6, IFN-γ and lysozyme in serum and BAL samples were measured by ELISA. Statistical analyses were performed using SPSS software. Results: Serum MIF had a remarkable positive correlation with IL-10 and IFN-γ but had a negative correlation with serum IgG levels. Importantly, longitudinal follow-up showed a positive correlation between MIF and % predicted diffusion capacity (%DLCO) at 3-year. Serum IL-18 had a significant positive correlation with serum lysozyme, but a negative correlation with % predicted total lung capacity at 3-year follow up. We identified two groups of sarcoidosis subjects with distinct clinical and cytokine features. A group with prominent extrapulmonary involvement, and low serum MIF, IL-10 and IFN-γ levels and a group with elevated serum MIF, IL-10 and IFN-γ levels. Moreover, we found a negative correlation between BAL IL-18 and BAL MIF in sarcoidosis subjects.Conclusions: Patients with low serum MIF, IL-10 and IFN-γ levels has severe and mostly extrapulmonary sarcoidosis with elevated lysozyme and IL-18 levels. Our work provides understanding of phenotypic diversity in association with heterogeneity in cytokine landscape in sarcoidosis.

Genetic Variation of Migration Inhibitory Factor Gene rs2070766 Is Associated With Acute Coronary Syndromes in Chinese Population

Genetic variation of macrophage migration inhibitory factor (MIF) gene has been linked to coronary artery disease. We investigated an association between the polymorphism of MIF gene rs2070766 and acute coronary syndromes (ACS) and the predictive value of MIF gene variation in clinical outcomes. This study involved in 963 ACS patients and 932 control subjects from a Chinese population. All participants were genotyped for the single nucleotide polymorphism (SNP) of MIF gene rs2070766 using SNPscan™. A nomogram model using MIF genetic variation and clinical variables was established to predict risk of ACS. Major adverse cardiovascular events (MACE) were monitored during a follow-up period. The frequency of rs2070766 GG genotype was higher in ACS patients than in control subjects (6.2 vs 3.8%, p = 0.034). Multivariate logistic regression analysis revealed that individuals with mutant GG genotype had a 1.7-fold higher risk of ACS compared with individuals with CC or CG genotypes. Using MIF rs2070766 genotypes and clinical factors, we developed a nomogram model to predict risk of ACS. The nomogram model had a good discrimination with an area under the curve of 0.781 (95% CI: 0.759–0.804), concordance index of 0.784 (95% CI: 0.762–0.806) and well-fitted calibration. During the follow-up period of 25 months, Kaplan-Meier curves demonstrated that ACS patients carrying GG phenotype developed more MACE compared to CC or CG carriers (p < 0.05). GG genotype of MIF gene rs2070766 was associated with a higher risk of ACS in a Chinese population. The GG genotype carriers in ACS patients had worse clinical outcomes compared with those carrying CC or CG genotype. Together with rs2070766 genetic variant of MIF gene, we established a novel nomogram model that can provide individualized prediction for ACS.

The role of macrophage migration inhibitory factor in predicting left ventricular remodeling in patients with acute myocardial infarction

Objective — to assess the role of circulating markers of inflammation and macrophage migration inhibitory factor (MIF) in the development of left ventricular (LV) remodeling 6 months after acute ST‑segment elevation myocardial infarction (STEMI). Materials and methods. The study involved 120 patients after STEMI and successful primary percutaneous coronary intervention (PCI). Transthoracic echocardiography with Doppler was performed within 24 — 48 hours after PCI and after 6 months of follow‑up to assess LV remodeling. The levels of MIF and inflammatory markers were measured before and after PCI. All patients were divided into two groups according to the median MIF level < 2501 pg/ml (first group, n = 60) and > 2501 pg/ml (second group, n = 60). Results. Patients with the high levels of circulating MIF had a higher frequency of complications in the hospital and long‑term periods (p = 0.024), including newly diagnosed heart failure or decompensation with hospitalizations. High MIF levels in patients of the second group were accompanied by a significant enlargement of end‑diastolic and end‑systolic LV volumes (p = 0.028; p = 0.031, respectively), the development of secondary mitral regurgitation (p = 0.024) and decreased LV systolic function (p = 0.037). MIF threshold values for predicting remodeling > 2694 pg/ml (sensitivity 69.2 %, specificity 71.4 %, AUC = 0.714; 95 % CI 0.509 — 0.870; p = 0.0375) and LV dysfunction > 2484 pg/ml (sensitivity 90.0 %, specificity 58.0 %, AUC = 0.782; 95 % CI 0.675 — 0.867, p = 0.0003) were determined using ROC analysis. According to the results of univariate and multivariate analysis, levels of MIF (p = 0.028) and soluble suppressor of tumorigenesis‑2 (p = 0.042) were most significant predictors of LV remodeling. A correlation between the levels of MIF and white blood cells count (r = 0.33, p = 0.0001), C‑reactive protein (r = 0.19, p = 0.032), troponin (r = 0.44, p = 0.002) has been established. Conclusions. An early increase of MIF levels is associated with the development of adverse structural and functional changes in left ventricle of patients after acute ST‑segment elevation myocardial infarction.

Modulatory Role of Macrophage Migration Inhibitory Factor on Cytokines and Clinical Features of Sarcoidosis

Background: Sarcoidosis is a systemic granulomatous disease of unknown etiology with a significant heterogeneity in organ manifestations, severity, and clinical course. Subjects with sarcoidosis share several features such as, non-necrotizing granuloma, hypergammaglobulinemia, increased local and circulating inflammatory cytokines, such as interleukin (IL)-6, IL-18, and interferon gamma (IFN-γ). Macrophage migration inhibitory factor (MIF) is a pluripotent chemokine produced by various cell types. The expression of MIF at sites of inflammation suggests a regulatory role in the function of macrophages. The objective of this study was to investigate the role of MIF in the serum and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients in association with clinical features and other cytokines. Methods: Sera and BALs of sarcoidosis patients (n=55) were collected at the time of diagnosis and patients were followed longitudinally for 3 years. Additionally, fifteen healthy controls participated in the study. The medical records of all patients including, demographics, radiography stages, pulmonary function tests, and organ involvements were recorded. The levels of MIF, IL-18, IL-10, IL-6, IFN-γ and lysozyme in serum and BAL samples were measured by ELISA. Statistical analyses were performed using SPSS software. Results: Serum MIF had a remarkable positive correlation with IL-10 and IFN-γ but had a negative correlation with serum IgG levels. Importantly, longitudinal follow-up showed a positive correlation between MIF and % predicted diffusion capacity (%DLCO) at 3-year. Serum IL-18 had a significant positive correlation with serum lysozyme, but a negative correlation with % predicted total lung capacity at 3-year follow up. We identified two groups of sarcoidosis subjects with distinct clinical and cytokine features. A group with prominent extrapulmonary involvement, and low serum MIF, IL-10 and IFN-γ levels and a group with elevated serum MIF, IL-10 and IFN-γ levels. Moreover, we found a negative correlation between BAL IL-18 and BAL MIF in sarcoidosis subjects.Conclusions: Patients with low serum MIF, IL-10 and IFN-γ levels has severe and mostly extrapulmonary sarcoidosis with elevated lysozyme and IL-18 levels. Our work provides understanding of phenotypic diversity in association with heterogeneity in cytokine landscape in sarcoidosis.