Elevated Macrophage Migration Inhibitory Factor Levels Research Articles

Macrophage migration inhibitory factor (MIF) suppresses mitophagy through disturbing the protein interaction of PINK1-Parkin in sepsis-associated acute kidney injury

Damage to renal tubular epithelial cells (RTECs) signaled the onset and progression of sepsis-associated acute kidney injury (SA-AKI). Recent research on mitochondria has revealed that mitophagy plays a crucial physiological role in alleviating injury to RTECs and it is suppressed progressively by the inflammation response in SA-AKI. However, the mechanism by which inflammation influences mitophagy remains poorly understood. We examined how macrophage migration inhibitory factor (MIF), a pro-inflammatory protein, influences the PINK1-Parkin pathway of mitophagy by studying protein–protein interactions when MIF was inhibited or overexpressed. Surprisingly, elevated levels of MIF were found to directly bind to PINK1, disrupting its interaction with Parkin. This interference hindered the recruitment of Parkin to mitochondria and impeded the initiation of mitophagy. Furthermore, this outcome led to significant apoptosis of RTECs, which could, however, be reversed by an MIF inhibitor ISO-1 and/or a new mitophagy activator T0467. These findings highlight the detrimental impact of MIF on renal damage through its disruption of the interaction between PINK1 and Parkin, and the therapeutic potential of ISO-1 and T0467 in mitigating SA-AKI. This study offers a fresh perspective on treating SA-AKI by targeting MIF and mitophagy.

High circulating MIF levels indicate the association with atypical antipsychotic-induced adverse metabolic effects.

Atypical antipsychotics (AAPs) are primary medications for schizophrenia (SZ). However, their use is frequently associated with the development of adverse metabolic effects, and the mechanisms behind these negative effects remain inadequately elucidated. To investigate the role of macrophage migration inhibitory factor (MIF) in regulating antipsychotic-induced metabolic abnormalities, between 2017 and 2020, a cross-sectional study was conducted, involving 142 healthy individuals and 388 SZ patients undergoing treatment with either typical antipsychotic (TAP) or AAP medications. Symptoms of SZ patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), and measurements of metabolic indices and plasma MIF levels were performed on all individuals. A significant increase in plasma MIF levels was observed in groups receiving five major AAP monotherapies in comparison to healthy controls (all p < 0.0001). There was no such increase shown in the group receiving TAP treatment (p > 0.05). Elevated plasma MIF levels displayed a notable correlation with insulin resistance (β = 0.024, p = 0.020), as well as with the levels of triglycerides (β = 0.019, p = 0.001) and total cholesterol (β = 0.012, p = 0.038) in the groups receiving AAPs. However, while the TAP group also displayed certain metabolic dysfunction compared to healthy controls, no significant association was evident with plasma MIF levels (all p > 0.05). In conclusion, plasma MIF levels exhibit a distinctive correlation with metabolic abnormalities triggered by AAPs. Hence, there is potential for further development of MIF as a distinctive marker for monitoring adverse metabolic effects induced by AAPs in clinical settings.

The Macrophage migration inhibitory factor is a vital player in Pan-Cancer by functioning as a M0 Macrophage biomarker

BackgroundThe role of the macrophage migration inhibitory factor (MIF) has recently attracted considerable attention in cancer research; nonetheless, the insights provided by current investigations remain constrained. Our main objective was to investigate its role and the latent mechanisms within the pan-cancer realm. MethodsWe used comprehensive pan-cancer bulk sequencing data and online network tools to investigate the association between MIF expression and patient prognosis, genomic instability, cancer cell stemness, DNA damage repair, and immune infiltration. Furthermore, we validated the relationship between MIF expression and M0 macrophages using single-cell datasets, the SpatialDB database, and fluorescence staining. Additionally, we assessed the therapeutic response using the ROC plotter tool. ResultsWe observed the upregulation of MIF expression across numerous cancer types. Notably, elevated MIF levels were associated with a decline in genomic stability. We found a significant correlation between increased MIF expression and increased expression of mismatch repair genes, stemness features, and homologous recombination genes across diverse malignancies. Subsequently, through an analysis using ESTIMATE and cytokine results, we revealed the involvement of MIF in immune suppression. Then, we validated MIF as a hallmark of the M0 macrophages involved in tumor immunity. Our study suggests an association with other immune-inhibitory cellular populations and restraint of CD8 + T cells. In addition, we conducted a comparative analysis of MIF expression before and after treatment in three distinct sets of therapy responders and non-responders. Intriguingly, we identified notable disparities in MIF expression patterns in bladder urothelial carcinoma and ovarian cancer following particular therapeutic interventions. ConclusionComprehensive pan-cancer analysis revealed notable enrichment of MIF within M0 macrophages, exerting a profound influence on tumor-associated immunosuppression and the intricate machinery of DNA repair.

Modulatory role of macrophage migration inhibitory factor on cytokines and clinical features of sarcoidosis

Sarcoidosis is a systemic granulomatous disease of unknown etiology with significant heterogeneity in organ manifestations and clinical course. Subjects with sarcoidosis share several features such as, non-necrotizing granuloma, hypergammaglobulinemia, increased local and circulating inflammatory cytokines. Macrophage migration inhibitory factor (MIF) is a pluripotent chemokine modulating cellular function. Study included healthy controls (n = 28) and sarcoidosis patients (n = 65). Sera and BAL of sarcoidosis patients were collected and patients were followed longitudinally for 3 years, and demographics, stages, pulmonary function tests, and organ involvements were recorded. We evaluated MIF in the serum and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients in association with clinical features and cytokines, IL-18, IL-10, IL-6, IFN-γ. We found serum MIF had a positive correlation with IL-10 and IFN-γ and % predicted total lung capacity (%TLC). Serum IL-18 had a significant positive correlation with serum lysozyme, but a negative correlation with %TLC and %DLCO. 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 and a group with elevated serum MIF, IL-10 and IFN-γ levels. Our work provides understanding of phenotypic diversity in association with heterogeneity in cytokine landscape in sarcoidosis.

Impact of Macrophage Migration Inhibitory Factor Gene Polymorphisms and Serum Macrophage Migration Inhibitory Factor Levels on Pulmonary and Spinal Tuberculosis Susceptibility: A Pooled Analysis.

Objective: This study was designed to evaluate the association between macrophage migration inhibitory factor (MIF) gene polymorphisms, serum MIF levels and tuberculosis (TB) susceptibility. Methods: All satisfactory studies were included; the MIF genotype number and serum MIF levels were reviewed. The Stata and Review Manager software were used for the pooled analyses. Results: The pooled analyses showed that the MIF-173G/C gene polymorphism was associated with TB (allele C vs allele G: odds ratio (OR) = 1.44, 95% confidence interval (CI): 1.28-1.62, p < 0.01; genotype CC vs genotype GG: OR = 1.69, 95% CI: 1.05-2.73, p = 0.03; genotype CC+GC vs genotype GG: OR = 1.56, 95% CI: 1.34-1.81, p < 0.01; genotype GC vs genotype GG: OR = 1.50, 95% CI: 1.28-1.75, p < 0.01). The subgroup analysis showed that the MIF-173G/C gene polymorphism was significantly associated with the risk of both pulmonary tuberculosis (PTB) and spinal tuberculosis (STB).The MIF CATT-794 gene polymorphism was associated with the PTB susceptibility in Asian subjects (genotypes 5/X+6/X vs genotypes 7/X+8/X: OR = 0.39, 95% CI: 0.24-0.64, p < 0.01; genotypes 5 + 6 vs genotypes 7 + 8: OR = 0.57, 95% CI: 0.48-0.69, p < 0.01). Both PTB and STB patients had significantly elevated serum MIF levels compared to healthy controls. Conclusion: The MIF-173G/C gene polymorphism is related to both PTB and STB susceptibility in both Asian and Caucasian populations. The C allele and CC genotype of the MIF-173G/C SNP appear to be TB risk factors. The MIF CATT-794 gene polymorphism is associated with the PTB susceptibility in Asian subjects; serum MIF levels were significantly increased in PTB and STB patients.

Difference in macrophage migration inhibitory factor between preterm and term newborns and associating clinical factors: Preliminary study.

This study aimed to investigate the macrophage migration inhibitory factor (MIF) and associated clinical factors in neonates. Clinical information and blood samples were obtained from 77 neonates. Clinical details were reviewed from medical records, and MIF was measured by enzyme-linked immunosorbent assay using blood samples acquired within a week after birth. Statistical analyses were performed between plasma MIF concentration and clinical factors. Among the 77 newborn infants, 25 were born at <34 weeks of gestation (preterm), 25 at 34 to 37 weeks (late preterm), and 27 at term gestation. The mean MIF was 9849.5 ± 7187.8 pg/mL in preterm, 5718.7 ± 4596.4 in late preterm, and 5361.1 ± 3895.7 in term infants (P = .016). Among 25 preterm infants born at <34 weeks of gestation, MIF was significantly higher in infants with necrotizing enterocolitis (NEC, 19,478.6 ± 8162.4 pg/mL, n = 5) than that in infants without NEC (feeding intolerance 7173.7 ± 4203.0 pg/mL, n = 12 and others 7844.9 ± 5311.2 pg/mL, n = 8, P = .020). Elevated plasma MIF levels in the transitional period were significantly associated with preterm birth before 34 weeks of gestation and the development of NEC.

CD74 ablation rescues type 2 diabetes mellitus-induced cardiac remodeling and contractile dysfunction through pyroptosis-evoked regulation of ferroptosis

Type 2 diabetes mellitus (T2D) contributes to sustained inflammation and myopathic changes in the heart although the precise interplay between the two remains largely unknown. This study evaluated the impact of deficiency in CD74, the cognate receptor for the regulatory cytokine macrophage migration inhibitory factor (MIF), in T2D-induced cardiac remodeling and functional responses, and cell death domains involved. WT and CD74-/- mice were fed a high fat diet (60% calorie from fat) for 8 weeks prior to injection of streptozotocin (STZ, 35 mg/kg, i.p., 3 consecutive days) and were maintained for another 8 weeks. KEGG analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis in T2D mouse hearts. T2D patients displayed elevated plasma MIF levels. Murine T2D exerted overt global metabolic derangements, cardiac remodeling, contractile dysfunction, apoptosis, pyroptosis, ferroptosis and mitochondrial dysfunction, ablation of CD74 attenuated T2D-induced cardiac remodeling, contractile dysfunction, various forms of cell death and mitochondrial defects without affecting global metabolic defects. CD74 ablation rescued T2D-evoked NLRP3-Caspase1 activation and oxidative stress but not dampened autophagy. In vitro evidence depicted that high glucose/high fat (HGHF) compromised cardiomyocyte function and promoted lipid peroxidation, the effects were ablated by inhibitors of NLRP3, pyroptosis, and ferroptosis but not by the mitochondrial targeted antioxidant mitoQ. Recombinant MIF mimicked HGHF-induced lipid peroxidation, GSH depletion and ferroptosis, the effects of which were reversed by inhibitors of MIF, NLRP3 and pyroptosis. Taken together, these data suggest that CD74 ablation protects against T2D-induced cardiac remodeling and contractile dysfunction through NLRP3/pyroptosis-mediated regulation of ferroptosis.

Serum Levels of HCY, MIF, and hs-CRP Correlate with Glycolipid Metabolism in Adults with Never-Medicated First-Episode Schizophrenia.

Objective It has been reported that the prevalence of metabolic syndrome (MS) in multiepisode patients with schizophrenia is 35.3%, which is 2- to 4-fold higher than in the general population. The study is designed to compare the glycolipid metabolism in patients with first-episode schizophrenia (FES) with sex- and age-matched healthy controls to investigate changes in serum levels of homocysteine (Hcy), macrophage migration inhibitory factor (MIF), and high-sensitive C-reactive protein (hs-CRP) and their relationships with the glycolipid metabolism in patients with FES. Methods His case-control study included 88 patients diagnosed with FES and 88 sex- and age-matched healthy controls. Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS), and 17-item Hamilton Rating Scale for Depression (HAMD-17). Patients with FES were classified into MS and non-MS groups. Results There were significant differences in the education level, body mass index (BMI), and waist circumference between the patients with FES and healthy controls (all p > 0.05). The patients with FES had higher levels of FPG and blood glucose at the oral glucose tolerance test (OGTT) (2 h glucose) concomitant with higher proportion of impaired glucose tolerance (IGT) and homeostasis model assessment of insulin resistance (HOMA2-IR) than healthy controls (all p < 0.001). It was revealed that the patients with FES showed higher serum levels of Hcy, MIF, and hs-CRP than healthy controls (all p < 0.001). The serum level of Hcy shared positive correlations with the score of PANSS totals (r = 0.551) and the negative syndrome of the PANSS scale (r = 0.494). The serum levels of MIF and hs-CRP was only positively correlated with the negative syndrome of the PANSS scale (r = 0.320 and r = 0.446). The level of Hcy shared positive correlations with the levels of FPG, 2 h glucose, and HOMA2-IR; the level of MIF was only positively correlated with the level of HOMA2-IR; the level of hs-CRP had a positive correlation with both levels of FPG and 2 h glucose (all p < 0.001). The levels of Hcy, MIF, and hs-CRP all shared positive correlations with the TG level and negative correlations with the HDL-C level (all p < 0.001). There were remarkable differences between the MS and non-MS groups with regard to BMI, waist circumference, negative subscale of the PANSS scale, FPG, TG, and HDL-C (all p < 0.05). Elevated levels of Hcy, MIF, and hs-CRP were detected in the MS group compared to the non-MS group (all p < 0.05). Conclusion These findings suggest that increased concentrations of HCY, MIF, and hs-CRP may contribute to the abnormal glycolipid metabolism in the context of schizophrenia.

Anti-Mullerian Hormone and Macrophage Migration Inhibitory Factor Determine the Reproductive Health of Ladakhi Women Residing at 3,500 m.

Shaw, Snigdha, Himashree Gidugu, Gopinath Bhaumik, Maramreddy Prasanna Kumar Reddy, Usha Panjwani, and Dishari Ghosh. Anti-Mullerian hormone and macrophage migration inhibitory factor determine the reproductive health of Ladakhi women residing at 3,500 m. High Alt Med Biol. 22:317-326, 2021. Background: Reproductive health of Ladakhi high-altitude (HA) native females was investigated for the first time in this study. Available literature suggest that, female reproductive cycle and hormonal profile varies in different HA populations due to heterogeneity. Although these studies illustrate some progress on the role of HA hypoxia, it still leaves scope for evaluation of the remaining mechanisms involved in the maintenance of reproductive health in this contemporary population. Materials and Methods: Menstrual details, phasic variations in circulatory steroid hormones, and gonadotropins along with oxytocin in sea level (SL) and HA (∼3,500 m) native females of India were assessed. Moreover, ovarian reserve marker anti-Mullerian hormone (AMH) and proinflammatory cytokine macrophage migration inhibitory factor (MIF) were measured. Results: A difference in Ladakhi women was registered compared to SL, regarding luteinizing hormone (LH) (2.6 mIU/ml vs. 4.4 mIU/ml, p < 0.05) and progesterone (P) (4.1 ng/ml vs. 9.4 ng/ml, p < 0.05) levels in their luteal phase. Reduced LH might contribute to poor development of the ovarian corpus luteum, subsequently diminish P level. Decreased AMH level in three age groups: 21-30 years (1.4 ng/ml vs. 3.2 ng/ml, p < 0.01), 31-40 years (0.6 ng/ml vs. 2.1 ng/ml, p < 0.01), and >40 years (0.4 ng/ml vs. 1.7 ng/ml, p < 0.01) of Ladakhi women were recorded than their SL counterpart. Elevated oxytocin (83.5 ng/ml vs. 76.3 ng/ml, p < 0.05) and MIF levels (70.2 ng/ml vs. 49.7 ng/ml, p < 0.01) along with low P and AMH levels delineated the reason for recorded early menopause (43.9 years), shorter reproductive span (∼29 years), and history of miscarriage in HA dwellers compared to SL. Conclusion: Therefore, the findings insinuated that the response of the reproductive system to hypoxia in Ladakhi women differs from SL women, and the adaptive response in these women might be in favor of their reproductive health.

A macrophage migration inhibitory factor as a predictor of reperfusion myocardial injury in patients with st-segment elevation myocardial infarction

Abstract Introduction Major adverse cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI) are still common despite the modern treatment approaches. It may be caused by the “no-reflow” phenomenon. One of the promising biomarkers for the coronary “no-reflow” phenomenon prediction is proinflammatory cytokine macrophage migration inhibitory factor (MIF). Purpose To estimate the role of MIF in the prediction of early reperfusion myocardial injury in patients with STEMI. Methods The study involved 341 STEMI patients (78.6% male and 21.4% female) with an average age of 59.08±9.65 years. Control group of 12 healthy volunteers included. All patients were made to undergo a baseline investigation. In addition, the level of MIF determined twice during the first 12 hours of STEMI, before the percutaneous coronary intervention (PCI) and after the procedure. Coronary blood flow evaluated using TIMI flow grade and myocardial blush grade (MBG). All patients had epicardial blood flow TIMI 3. The criteria for “no-reflow” diagnosis were myocardial perfusion at MBG 0 or MBG 1 level with complete recovery of epicardial blood flow or ST-segment resolution (rST) of less than 70% from baseline within 2 hours after PCI. All patients were divided into two groups according to MBG and rST after PCI more and less than 70%: 147 patients in the first group with MBG stage 0–1, 182 patients with MBG stage 2–3 Results 64% of STEMI patients had elevated MIF levels above the highest value in healthy controls (2778±217 ng/ml; 225±6,7 ng/ml; p=0,0003). The level of MIF biomarker, determined before PCI was significantly higher in the group of patients with MBG 0–1 in comparison to MBG 2–3. (4708±471 ng/ml vs 2914±347ng/ml; p=0,004). Using the multivariate regression analysis, the dependencies of the biomarker MIF on the parameters of the reperfusion myocardial injuries were obtained. MIF measured before revascularization as well as the patient's gender, was an independent predictor of MBG 0–1 and rST less than 70% (coefficients Beta 0,1; odd ratio 1,1; 95%confidential interval (CI) 1,0–1,2; p=0,037 and coefficient Beta 2,9; odd ratio 17.7; 95% CI 0,96–32; p=0,05, respectively). Conclusions The study revealed that MIF predicts reperfusion myocardial injury in patients with STEMI. Future investigations of the MIF biological effects are the perspective direction in the field of modern cardiology. Funding Acknowledgement Type of funding source: None

P6604Role of macrophage migration inhibitory factor and early after infarction remodeling in patients with ST-segment elevation myocardial infarction

Abstract A heart failure formation in patients with ST-segment elevation myocardial infarction (STEMI) is the most often adverse outcome and determined by early cardiac remodeling. One of the promising biomarkers for the early diagnosis of cardiac remodeling is proinflammatory cytokine macrophage migration inhibitory factor (MIF). Purpose estimate the role of MIF in the prediction of early cardiac remodeling in patients with STEMI. Methods The study involved 73 STEMI patients (72.6% male and 27.4% female) with an average age of 58.25±10.45 years. Control group of 12 healthy volunteers included. All patients were made to undergo a baseline investigation. In addition, the level of MIF determined during the first 12 hours of STEMI and before the percutaneous coronary intervention. Results 64% of STEMI patients had elevated MIF levels above the highest value in healthy controls (2778±217 ng/ml; 225±6,7 ng/ml; p=0,0003). Using the linear regression analysis, the dependences of the biomarker MIF on the parameters of the left ventricle end-diastolic volume and the left ventricle end-systolic volume obtained (dependent variables, standardized coefficients beta −1.1; p=0.001 and 0.6; p=0.02, respectively). Conclusions STEMI patients with higher MIF concentration associated with more pronounced changes in heart geometry during the acute period. Further investigations of the MIF biological effects are the perspective direction in the development of prevention and treatment of STEMI.

Assessment of macrophage migration inhibitory factor in patients with verruca vulgaris.

BackgroundCommon 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.ObjectiveTo 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 methodsA 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.ResultsSignificant high MIF levels were detected in lesional and perilesional skin biopsies compared to controls (P<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, P=0.021).ConclusionThe significantly elevated MIF levels in lesional and perilesional skin biopsies compared to controls point to its role in wart progression from HPV infected cells.

Fenofibrate attenuates fatty acid-induced islet β-cell dysfunction and apoptosis via inhibiting the NF-κB/MIF dependent inflammatory pathway

BackgroundFatty acid-induced lipotoxicity and macrophage migration inhibitory factor (MIF) affect pancreatic β-cell function, and may promote the development of diabetes mellitus. However, the association of lipotoxicity with MIF and the effect of Fenofibrate on β-cell function remain unknown. MethodsLPL+/− mice and MIN6 cells stimulated with palmitic acid (PA) were utilized as models of lipid metabolism disorders. Factors associated with insulin secretion and apoptosis were assessed in the presence or absence of Fenofibrate. The possible mechanisms of lipotoxicity-induced β-cell dysfunction were also explored. ResultsFenofibrate effectively improved lipid accumulation in pancreatic β-cells, increased glucose-stimulated insulin secretion and β-cell mass, and significantly downregulated pro-apoptotic molecules, at the gene and protein levels, both in vivo and in vitro. Additionally, elevated MIF levels in serum from LPL+/− mice and PA-treated MIN6 cells were starkly decreased after Fenofibrate administration. Mechanistic analysis indicated that NF-κB signaling was remarkably triggered, which could further activate MIF transcription. Furthermore, Fenofibrate exerted beneficial effects on fatty acid-induced β-cell dysfunction likely by inhibiting the NF-κB/MIF dependent inflammatory response. ConclusionsFenofibrate ameliorates lipotoxicity-induced β-cell dysfunction and apoptosis by inhibiting the NF-κB/MIF inflammatory pathway. These findings provide novel insights into the treatment of lipotoxicity-induced metabolic disorders.

Urinary Macrophage Migration Inhibitory Factor as a Noninvasive Biomarker in Pediatric Henoch-Schönlein Purpura Nephritis.

The aims of this study were to investigate urinary macrophage migration inhibitory factor (MIF) levels and their clinical significance in Henoch-Schönlein purpura (HSP) children with or without nephritis (N) and to assess the influence of steroid treatment on the urine MIF levels of HSPN patients. Group I comprised 35 children with HSPN who were examined twice (A before treatment and B after steroid treatment). Group II comprised 41 children with HSP. The control group included 32 healthy children. Urinary MIF levels were measured via enzyme linked immunosorbent assay. The levels of serum creatinine, blood urea nitrogen, urinary microalbumin (mAlb), and 24-hour proteinuria were performed to determine their associations with MIF levels. Urinary MIF levels were significantly higher in group I compared with group II and the control group (P < 0.01); however, no significant difference was found between group II and the control group (P > 0.05). Upon examination, albeit urinary MIF concentration was significantly lower in group IB compared with group IA (P < 0.05), these concentrations were statistically higher than that of group II (P < 0.05). In addition, in the HSPN patients, the urinary MIF was positively associated with urinary microalbumin and 24-hour proteinuria but no association with serum creatinine and blood urea nitrogen. Elevated urinary MIF levels were found to be correlated with proteinuria in pediatric HSPN. An obvious decrease in urinary MIF concentrations among the children with HSPN was associated with steroid treatment. Urinary MIF can be used as a noninvasive biomarker in pediatric HSPN.

Elevated MIF-2 levels predict mortality in critically ill patients

PurposeD-dopachrome tautomerase (MIF-2 or DDT) is a member of the macrophage migration inhibitory factor (MIF) superfamily and a close structural homolog to MIF. Circulating MIF-2 has been described to be elevated in patients suffering from sepsis, severe burn injury and after surgery. We sought to evaluate the prognostic value of MIF-2 in critically ill patients. MethodsA total of 72 patients were studied upon admission to the medical intensive care unit (ICU). MIF and MIF-2 levels were assessed and compared to healthy controls. Clinical data, various laboratory parameters and mortality were assessed. ResultsWe found significantly elevated levels of MIF-2 and MIF at admission to the ICU in critically ill patients compared to healthy controls. MIF-2 levels were associated with disease severity as measured by APACHE II scores. MIF-2 levels in ICU patients correlated with biomarkers reflecting organ damage, but were not influenced by acute or chronic kidney disease. Kaplan-Meier analysis revealed distinctly elevated mortality in patients with high plasma MIF-2 levels. ConclusionsMIF-2 levels are elevated in critically ill patients and linked to parameters of organ damage, supporting its value as a potential tool for the assessment of prognosis in critical illness.

Renal replacement therapy neutralizes elevated MIF levels in septic shock.

BackgroundMacrophage migration inhibitory factor (MIF) is known to amplify the immune response in septic animal models. Few clinical data support this pro-inflammatory role in septic patients. Renal replacement therapy (RRT) as adjuvants in the complex therapy of sepsis has been proposed as a possible approach to eliminate elevated circulating cytokines. Since recent data suggest that MIF can be effectively removed from the circulating blood pool in patients with chronic kidney disease, we here aimed to investigate whether RRT in septic shock can lower plasma levels of this pro-inflammatory cytokine in septic shock patients.MethodsAn observational single-center study on an internist intensive care unit (ICU) was conducted. MIF plasma levels and mortality of n = 25 patients with septic shock were assessed with a previously validated method for reliable MIF values. The effect of continuous renal replacement therapy (CRRT) on daily MIF levels and mortality was assessed by comparing patients with and without need for CRRT due to acute kidney injury (AKI).ResultsMIF plasma levels in patients undergoing CRRT due to septic AKI were steadily decreased compared to those from patients without CRRT hinting at a MIF removal by hemodialysis. MIF release during ICU stay as assessed by MIFAUC was lower in patients undergoing CRRT, and Kaplan-Meier analysis revealed a distinctly lower mortality in patients undergoing CRRT. Analysis of daily MIF levels showed that patients who did not survive septic shock exhibited steadily higher MIF plasma levels and higher MIFAUC compared to those surviving sepsis. Low MIF levels were closely associated with improved survival.ConclusionsThis is the first study investigating the effect of efficient MIF removal from the plasma pool of patients with septic shock. Reduction of high circulating MIF by CRRT therapy was accompanied by improved survival. Thus, targeted removal of MIF from the circulating blood pool might be a promising approach to reduce mortality in severe sepsis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40560-016-0163-2) contains supplementary material, which is available to authorized users.

Inhibition of Macrophage Migration Inhibitory Factor Protects against Inflammation and Matrix Deposition in Kidney Tissues after Injury.

Background. Macrophage migration inhibitory factor (MIF) is an important immunoregulatory cytokine involved in inflammation, which may be one important reason resulting in matrix deposition in renal tissues after injury. However, the underlying mechanisms have not yet been elucidated. Methods and Results. We uncovered a crucial role of MIF in inflammation and collagen deposition in vivo and in vitro. In rats, ureteral obstruction induced tubular injury, matrix accumulation, and inflammatory cell infiltration. Additionally, enhanced MIF levels in the obstructed kidneys were closely related to the increasing numbers of CD68-positive macrophages. These obstruction-induced injuries can be relieved by recanalization, consequently resulting in downregulated expression of MIF and its receptor CD74. Similarly, ischemia reperfusion induced renal injury, and it was accompanied by elevated MIF levels and macrophages infiltration. In cultured tubular epithelial cells (TECs), aristolochic acid (AA) promoted matrix production and increased MIF expression, as well as the release of macrophage-related factors. Inhibition of MIF with an antagonist ISO-1 resulted in the abolishment of these genotypes in AA-treated TECs. Conclusion. MIF plays an important role in macrophage-related inflammation and matrix deposition in kidney tissues following injury. MIF as a specific inhibitor may have therapeutic potential for patients with inflammatory and fibrotic kidney diseases.

The role of macrophage migration inhibitory factor in critical illness.

Emerging evidence suggests a pivotal role of macrophage migration inhibitory factor (MIF) in the systemic inflammatory immune response. MIF is located in various cell types and rapidly released after different stimuli like inflammation, surgical stress or ischemia and reperfusion. MIF is a known key player in the inflammatory response and contributes to several biological functions including the control of cell cycle (through activation of ERK1/2), sensing of pathogen stimuli (upregulation of TLR4 expression), recruitment of various immune cells (neutrophils, monocytes) and prevention of p53-mediated apoptosis of macrophages. While MIF`s pro-inflammatory effects are crucial for an effective host defense, elevated MIF levels were repeatedly shown to be associated with the development of organ dysfunction and deleterious sequelae. Even more puzzling, increasing evidence indicates a protective role of this pleiotropic cytokine during ischemia and reperfusion injury in the myocardium. This review focuses on new insights regarding the biological significance of MIF release in the context of critical illness and ischemia/ reperfusion.

A case-control study on the association of MIF -794 CATT5-8 and -173 G&gt;C polymorphisms and its serum levels and the clinical severity of multiple sclerosis in Mexican patients

Event Abstract Back to Event A case-control study on the association of MIF -794 CATT5-8 and -173 G>C polymorphisms and its serum levels and the clinical severity of multiple sclerosis in Mexican patients Victor A. Castaneda Moreno1, José F. Muñoz-Valle1*, Norma Torres Carrillo1, Oscar P. Gonzalez Perez1, 2, Miguel A. Macias Islas3, Jose L. Ruiz Sandoval4, Ofelia Padilla De La Torre3, Xochitl A. Trujillo Trujillo5 and Miguel Huerta Vieyra5 1 Universidad De Guadalajara, Mexico 2 Universidad de Colima, Mexico 3 Centro medico nacional de occidente, Neurologia Clinica, Mexico 4 Hospital Civil Fray Antonio Alcalde, Mexico 5 Universidad de Colima, Mexico The macrophage migration inhibitory factor (MIF), is one of the main cytokines involved in the tissular damage progression in several autoimmune diseases. This central role of MIF in inflammation and disease progression, suggest it might be a potential therapeutic target for multiple sclerosis (MS), however it is first necessary to know if it actually plays an important role on MS. We investigated whether the commonly occurring functional polymorphisms in the promoter of MIF have a significant impact on adults with MS in a Mexican Mestizo population. The patients for this study were recruited from the Centro Medico Nacional de Occidente, IMSS, in Guadalajara, Jalisco, Mexico, and the healthy subjects (HS) were recruited from the general population by invitation. A total of 200 patients and 200 HS were recruited from August 2013 to October 2014. Genotyping of -794 CATT5-8 (rs5844572) and -173 G>C (rs755622) polymorphisms was done through PCR and PCR-RFLP, respectively. MIF serum levels were determined by ELISA with a commercial kit provided by BioLegend. Statistical analysis was done with IBM’s SPSS v 20.0. Respect to the analysis of the serum levels of MIF there was significantly higher levels of MIF in MS patients (6.5 ng/ml) compared with HS (3.7 ng/ml) (p<0.01). We found a tendency to lower serum levels of MIF in patients that were on relapse (4.7 ng/ml) vs patients that were on remission (6.5 ng/ml), although this didn’t reach statistical significance (p=0.076). We also found a positive correlation (rs=0.267) between the serum levels of MIF on remission and the expanded disability status scale (EDSS) (p=0.009). On the analysis of the MIF polymorphisms genotypes and the clinical characteristics of MS patients, we found a significant association of the -173 GC genotype with a higher EDSS (p=0.027), as well as with a higher multiple sclerosis severity score (MSSS) (p=0.028). We also found an association of the -794 CATT 5/7 genotype with a higher MSSS (p<0.05). Finally, we found a significant association of the -794 CATT 5 allele with higher levels of MIF in serum of MS patients (carriers 7.59 ng/ml vs non carriers 5.35 ng/ml, p=0.026). In conclusion, elevated levels of MIF are associated with MS and seem to play a role in the disease progression as it rises in serum as increases EDSS. Also, the -794 CATT 5 allele is associated with higher MIF serum levels in MS, and the -794 CATT 5/7 genotype is associated with higher MSSS. Likewise, the -173 GC genotype is associated with higher EDSS and MSSS. However, further studies of other cytokines and their relationship with MIF are necessary to have a complete understanding of the role of this protein in MS. The present study was financed by the Consejo Nacional para la Ciencia y la Tecnología from Mexico, proyect number: 180663.

Developmental endothelial locus-1 inhibits MIF production through suppression of NF-κB in macrophages

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that regulates leukocyte recruitment, thereby playing a pivotal role in the regulation of innate and adaptive immunity and tumor progression. Elevated levels of MIF are associated with numerous inflammatory disorders and cancers. To determine whether developmental endothelial locus-1 (Del-1) regulated MIF, RAW264.7 macrophages were treated with Del-1 and assessed using ELISA. The results showed that MIF was downregulated in macrophages by Del-1, an endogenous anti-inflammatory protein that was previously shown to limit leukocyte adhesion and migration. Treatment of RAW264.7 macrophages with Del-1 inhibited constitutive and lipopolysaccharide (LPS)-induced MIF secretion. Recombinant Del-1 protein attenuated the phosphorylation of IκBα induced by a relatively low concentration of LPS in THP-1 monocytes, but did not inhibit IκBα phosphorylation in response to a relatively high concentration of LPS. Concomitantly, translocation of NF-κB to the nucleus was inhibited by Del-1 in LPS-activated macrophages. In addition, conditioned medium harvested from cells transfected with a Del-1 expression plasmid suppressed NF-κB activation in response to relatively low concentrations of TNF-α, albeit not the activation that was induced by a relatively high concentration of TNF-α. On the other hand, although Del-1 enhanced the macrophage expression of p53, a known negative regulator of MIF production, MIF production was not significantly affected by the level of p53 in mouse bone marrow-derived macrophages. These findings suggested that Del-1 controls NF-κB-activated MIF production in macrophages, and the potential application of Del-1 to therapeutic modalities for chronic inflammation-associated cancers.