Plasma Macrophage Migration Inhibitory Factor Levels Research Articles

Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia.

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.

Subjective Assessment Underestimates Fraility in Patients With Heart Failure Referred for Advanced Therapies.

Assessment of frailty is key for evaluation for advanced therapies (ATs). Most programs use a subjective provider assessment (SPA) or "eye-ball" test; however, objective measures exist. The modified five-item Fried Frailty Index (mFFI) is a validated tool to assess frailty. We compared SPA to mFFI testing in patients referred for AT. We also compared levels of macrophage migration inhibitory factor (MIF), an inflammatory biomarker associated with worse outcomes in heart failure, between frail and not frail subjects. Seventy-eight patients referred for evaluation for AT underwent both SPA and mFFI testing. Three cardiac surgeons independently assessed patients for frailty (SPA). SPA significantly underestimated frailty compared with mFFI testing and correlation between SPA and mFFI was not strong (κ = 0.02-0.14). Providers were correct 84% of the time designating a subject as frail, but only 40% of the time designating as not frail. Agreement between all three providers was robust (76%), which was primarily driven by designation as not frail. There was no significant difference in plasma MIF levels between frail and not frail subjects (47.6 ± 25.2 vs . 45.2 ± 18.9 ng/ml; p = 0.6). Clinicians significantly underestimate frailty but are usually correct when designating a patient as frail.

Macrophage migration inhibitory factor levels are associated with disease activity and possible complications in membranous nephropathy

Membranous nephropathy (MN) is an autoimmune disease characterized by the deposition of immunoglobulin G (IgG) and complementary components in the epithelium of the glomerular capillary wall. Macrophage migration inhibitory factor (MIF) is an inflammatory mediator released by macrophages. MIF plays a key regulatory function in the pathogenesis of immune-mediated glomerulonephritis. This study aimed to investigate whether MIF level could be associated with the activity of MN. Plasma and urine samples from 57 MN patients and 20 healthy controls were collected. The MIF levels in plasma and urine were determined by an enzyme-linked immunosorbent assay (ELISA) kit. The expression of MIF in the renal specimens from 5 MN patients was detected by immunohistochemistry (IHC). The associations of the plasma and urinary levels of MIF and glomerular MIF expression with clinical and pathological characteristics were analyzed. It was revealed that with the increase of MIF levels in plasma and urine, the severity of renal pathological injury in MN patients gradually increased. Correlation analysis showed that the MIF levels in plasma were positively correlated with the platelet (PLT) count (r = 0.302, P = 0.022), and inversely correlated with the prothrombin time (PT) (r = − 0.292, P = 0.028) in MN patients. The MIF levels in plasma were positively correlated with the C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) (r = 0.651, P < 0.0001; r = 0.669, P < 0.0001) in MN patients. The urinary levels of MIF were positively correlated with ESR (r = 0.562, P < 0.0001). IHC suggested that MIF was expressed in glomerular basement membrane and tubulointerstitial areas. MIF levels in plasma and urine could reflect the severity of MN, and MIF levels in plasma and urine could be associated with venous thrombosis and infectious complications in MN patients. The glomerular MIF expression could be used to indicate the activity of MN.

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.

Inhibition of Macrophage Migration Inhibitory Factor Activity Attenuates Haemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats.

ObjectiveThe aim of this study was to investigate (a) macrophage migration inhibitory factor (MIF) levels in polytrauma patients and rats after haemorrhagic shock (HS), (b) the potential of the MIF inhibitor ISO-1 to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) HS rat models and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in HS.BackgroundThe MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. MIF is a pleiotropic cytokine which can modulate the inflammatory response, however, its role in trauma is unknown.MethodsThe MIF levels in plasma of polytrauma patients and serum of rats with HS were measured by ELISA. Acute HS rat models were performed to determine the influence of ISO-1 on MODS. The activation of NF-κB and NLRP3 pathways were analysed by western blot in the kidney and liver.ResultsWe demonstrated that (a) MIF levels are increased in polytrauma patients on arrival to the emergency room and in rats after HS, (b) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (c) treatment of HS-rats with ISO-1 attenuated the organ injury and dysfunction in acute HS models and (d) reduced the activation of NF-κB and NLRP3 pathways in the kidney and liver.ConclusionOur results point to a role of MIF in the pathophysiology of trauma-induced organ injury and dysfunction and indicate that MIF inhibitors may be used as a potential therapeutic approach for MODS after trauma and/or haemorrhage.

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.

Plasma Macrophage Migration Inhibitory Factor Predicts Graft Function Following Kidney Transplantation: A Prospective Cohort Study.

Background: Delayed graft function (DGF) is a common complication after kidney transplantation (KT) with a poor clinical outcome. There are no accurate biomarkers for the early prediction of DGF. Macrophage migration inhibitory factor (MIF) release during surgery plays a key role in protecting the kidney, and may be a potential biomarker for predicting post-transplant renal allograft recovery.Methods: Recipients who underwent KT between July 2020 and December 2020 were enrolled in the study. Plasma MIF levels were tested in recipients at different time points, and the correlation between plasma MIF and DGF in recipients was evaluated. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2000035596).Results: Intraoperative MIF levels were different between immediate, slowed, and delayed graft function groups (7.26 vs. 6.49 and 5.59, P < 0.001). Plasma MIF was an independent protective factor of DGF (odds ratio = 0.447, 95% confidence interval [CI] 0.264–0.754, P = 0.003). Combining plasma MIF level and donor terminal serum creatinine provided the best predictive power for DGF (0.872; 95%CI 0.795–0.949). Furthermore, plasma MIF was significantly associated with allograft function at 1-month post-transplant (R2 = 0.42, P < 0.001).Conclusion: Intraoperative MIF, as an independent protective factor for DGF, has excellent diagnostic performance for predicting DGF and is worthy of further exploration.

197-LB: The Regulation of HSL by Macrophage Migration Inhibitory Factor (MIF) Contributes to Adipocyte Hypertrophy and Development of Obesity

Inflammation is associated with lipolysis in adipose tissue. HSL is a key enzyme in mediating lipolysis through augmenting hydrolysis of triglycerides and diacylglycerides. Our study found that the procytokine MIF has both transcriptional and non-transcriptional effects on mediating HSL through activating AMPK signaling pathway. The activated AMPK downregulates HSL gene expression in adipocytes. It also upregulates a phosphorylation of HSL Ser565, an inhibitory phosphorylation site, leading to the reduction of HSL active site, Ser563 phosphorylation. These mechanisms are operative in either transgenic overexpressed MIF mouse models or WT mice with high circulating MIF levels following a high caloric diet feeding (HFD). The MIF/AMPK/HSL axis regulates the development of adipocyte hypertrophy and obesity. We also confirm that high plasma MIF levels are associated with decreased adipose HSL gene expression in human obesity. Interestingly, in Mif-/-mice, HSL gene expression is also inhibited, suggesting that MIF genotype is important to maintain adipose HSL expression. Following HFD feeding, Mif-/-mice demonstrates higher Akt and lower PKA phosphorylation, which further decrease HSL activation and exacerbate obesity compared to WT. Thus, HSL regulation by MIF may be an important molecular mechanism in the development of obesity.View largeDownload slideView largeDownload slide DisclosureL. Chen: None. Y. Huang: None. L. Li: None. H. Zabihi: None. Y. Qi: None. L. Leng: None. G. Sun: None. R. Bucala: None. D. Qi: None.FundingNational Sciences and Engineering Research Council of Canada (RGPIN-2017-04542); Canadian Institutes of Health Research (PJT-156116)

44-OR: PAR2-Regulated MIF Secretion from Non-Immune Cells in Adipose Tissue Is a Key Mechanism Involved in the Development of Metabolic Dysfunction

Macrophage migration inhibitory factor (MIF) is a cytokine that is increased in obesity and contributes to metabolic dysfunction. Our present study describes a novel mechanism by which fatty acids activate non-immune cells to increase MIF secretion in adipose tissue, initiating cross-talk between preadipocytes and adipocytes. High fatty acids specifically induce protease-activated receptor 2 (PAR2) activation in preadipocytes, which downregulates pref-1 expression and release. Preadipocyte factor 1 (Pref-1) has an autocrine-paracrine action to inhibit the release of MIF from both preadipocytes and adipocytes. Thus, the loss of Pref-1 secretion during high fat feeding is responsible in part for both increased MIF secretion in adipose tissue and the rise in plasma MIF levels that ensues. The physiological consequences are most evident in adipose tissue. Genetic deletion of Par2 confirms the importance of this mechanism in mice, protecting against high fat diet-induced metabolic dysfunction. Importantly, this novel mechanism is also operative in adipose tissue from obese human subjects. These results provide the scientific rationale to consider whether strategies to either block Par2 expression or augment Pref-1 secretion might improve metabolic health in obesity or type 2 diabetes. Disclosure Y. Huang: None. L. Chen: None. Y. Qi: None. D. Qi: None.

Macrophage Migration Inhibitory Factor as a Predictor for Long-term Improvements After Mindfulness-Based Group Therapy or Treatment as Usual for Depression, Anxiety or Stress and Adjustment Disorders

ObjectivesIdentification of biological markers that can guide treatment selection is considered to be a viable solution for personalized treatment for patients with psychiatric disorders. This study investigated whether macrophage migration inhibitory factor (MIF) levels at baseline were associated with mindfulness-based group therapy or cognitive behavioral therapy response in patients with mild to moderate symptoms of depression, anxiety, or stress- and adjustment disorders.MethodsA total of 168 patients (aged 21–65 years) with psychiatric disorders were included from a randomized controlled trial. Plasma MIF levels in all the patients were analyzed using Luminex assay.ResultsHigher MIF levels at baseline were significantly associated with better long-term (1-year follow-up) improvement in psychiatric symptoms, as measured by changes in the Montgomery-Åsberg Depression Rating Scale (MADRS-S), compared with lower MIF levels, after adjustment for baseline MADRS-S score, age, sex, BMI, and pharmacotherapy (β = 5.89, p = 0.001). Patients with higher levels of MIF (8235–23,391 pg/ml) had an almost 6 points’ larger decrease in MADRS-S score after 1 year compared with those with lower MIF (727–8223 pg/ml) at baseline. Similar trends were seen after 8 weeks, albeit non-significant (β = 1.99, p = 0.18).ConclusionsThe findings indicate that higher plasma MIF levels at baseline may predict better long-term outcomes with psychotherapeutic interventions for mild to moderate symptoms of depression, anxiety, or stress and adjustment disorders. MIF levels may serve as a potential biomarker that can guide treatment selection for the personalized treatment for patients with psychiatric disorders.

2598. Macrophage Migration Inhibitory Factor May Contribute to Disseminated Coccidioidomycosis Susceptibility

BackgroundDisseminated coccidioidomycosis occurs in <1% of cases, and genetic polymorphisms may account for some of the variability in infection severity. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with two promoter polymorphisms linked to variability in expression. High expression MIF polymorphisms have been associated with granulomatosis with polyangitis (GPA), sarcoidosis and tuberculosis. Despite the overlap between MIF and Coccidioides immunity, MIF has never been studied in coccidioidomycosis.MethodsA549 cells transfected with MIF promoter/luciferase plasmids of 0 or 8 CATT repeats were stimulated with 50 µg/mL of inactivated C. posadasii spherule lysate, and luciferase expression was measured as relative units (RU) of luminescence. Genomic DNA from patients with disseminated coccidioidomycosis (n = 37) and healthy controls (n = 371) was analyzed for the 794 CATT5-8 microsatellite and the -173 G/C SNP. Cohorts were divided into self-identified African Americans and Caucasians, and allele frequencies were compared using Fisher exact test. Plasma MIF levels were analyzed by enzyme-linked immunosorbant assay using specific antibodies, and levels were compared by T-test.ResultsHuman lung epithelial cells exposed to Coccidioides spherules had significantly higher MIF expression than unexposed cells (3.94 ± 0.44 vs. 3.02 ± 0.24 RU, P = 0.0162). Among Caucasians (n = 26), the high MIF expression −173C containing genotype was present in 50% of the coccidioidomycosis patients vs. 40% of healthy controls (P = 0.396). The -794 CATT7 containing genotype was present in 40% of patients vs. 27% of controls (p = 0.240). Plasma MIF levels were higher in coccidoidomycosis patients with high- vs. low-expression alleles (P = 0.008), but lower in patients vs. controls (P < 0.0001).Conclusion Coccoidioides spherules stimulated MIF expression in human lung epithelial cells supporting the hypothesis that MIF is involved in immunity against this pathogen. In Caucasian subjects, the higher MIF expression genotypes were more common in patients with disseminated coccidioidomycosis when compared with healthy controls, although significance was limited by sample size. This is consistent with high expression MIF alleles associated with other granulomatous diseases, and may reflect destruction of the granuloma with pathogen dissemination.Disclosures All authors: No reported disclosures.

Circulating MIF Levels Predict Clinical Outcomes in Patients With ST-Elevation Myocardial Infarction After Percutaneous Coronary Intervention

BackgroundThe purpose of the study was to assess the value of admission macrophage migration inhibitory factor (MIF) levels in predicting clinical outcomes in ST-elevation myocardial infarction (STEMI) patients. MethodsFor this study we recruited 498 STEMI patients after they received percutaneous coronary intervention (PCI), 40 with stable angina pectoris and 137 healthy participants. Plasma MIF levels were measured at admission and after PCI. The primary end points were in-hospital mortality and major adverse cardio-and/or cerebrovascular events (MACCE) during hospitalization and 3.2-year follow-up period. ResultsAdmission MIF levels were elevated in 88.4% of STEMI patients over the upper reference limit of healthy controls and it was 3- to 7-fold higher than that in stable angina pectoris and control groups (122 ± 61 vs 39 ± 19 vs 17 ± 8 ng/mL; P < 0.001). Admission MIF levels were significantly higher in patients who died after myocardial infarction vs survivors. For predicting in-hospital mortality using the optimal cutoff value (127.8 ng/mL) of MIF, the area under the receiver operating characteristic curve for MIF was 0.820, similar area under the receiver operating characteristic curve values for predicting short-term outcomes were observed for high-sensitivity troponin T, CK-MB, N-terminal probrain natriuretic peptide, and Global Registry of Acute Coronary Events (GRACE) score. Although peak high-sensitivity troponin T and N-terminal probrain natriuretic peptide also predicted MACCE during the follow-up period, only higher admission MIF levels predicted in-hospital mortality and MACCE during the 3.2-year follow-up. Multivariate regression analysis showed the independent predictive value of a higher admission MIF level (≥ 127.8 ng/mL) on in-hospital mortality (odds ratio, 9.1; 95% confidence interval, 1.7-47.2) and 3.2-year MACCE (hazard ratio, 2.8; 95% confidence interval, 1.5-5.6). ConclusionsA higher admission MIF level is an independent predictor for in-hospital mortality and long-term MACCE in STEMI patients who underwent PCI.

Association between plasma macrophage migration inhibitor factor and deep vein thrombosis in patients with spinal cord injuries.

The patients with spinal cord injury (SCI) suffered significantly higher risk of deep vein thrombosis (DVT) than normal population. The aim was to assess the clinical significance of macrophage migration inhibitory factor (MIF) as the risk factor for DVT in acute SCI patients. 207 Chinese patients were enrolled in this study, including thirty-nine (39) patients (18.8 %; 95 %CI: 13.5 %–24.2 %) diagnosed as DVT at the follow-up of 1 month. Nine (9) of the 39 patients (23.1%) were suspected of thrombosis before the screening. The MIF levels in plasma of DVT patients were significantly higher than DVT-free patients. The risks of DVT would be increased by 11 % (OR unadjusted: 1.11; 95% CI, 1.06–1.17, P<0.001) and 8 % (OR adjusted: 1.08; 1.03–1.14, P=0.001), for each additional 1 ng/ml of MIF level. Furthermore, after MIF was combined with established risk factors, area under the receiver operating characteristic curve (standard error) was increased from 0.82(0.035) to 0.85(0.030). The results showed the potential association between the high MIF levels in plasma and elevated DVT risk in SCI patients, which may assist on early intervention.

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion.

Macrophage migration inhibitory factor (MIF) is pleiotropic cytokine that has multiple effects in many inflammatory and immune diseases. This study reveals a potential role of MIF in acute kidney injury (AKI) in patients and in kidney ischemic reperfusion injury (IRI) mouse model in MIF wild‐type (WT) and MIF knockout (KO) mice. Clinically, plasma and urinary MIF levels were largely elevated at the onset of AKI, declined to normal levels when AKI was resolved and correlated tightly with serum creatinine independent of disease causes. Experimentally, MIF levels in plasma and urine were rapidly elevated after IRI‐AKI and associated with the elevation of serum creatinine and the severity of tubular necrosis, which were suppressed in MIF KO mice. It was possible that MIF may mediate AKI via CD74/TLR4‐NF‐κB signalling as mice lacking MIF were protected from AKI by largely suppressing CD74/TLR‐4‐NF‐κB associated renal inflammation, including the expression of MCP‐1, TNF‐α, IL‐1β, IL‐6, iNOS, CXCL15(IL‐8 in human) and infiltration of macrophages, neutrophil, and T cells. In conclusion, our study suggests that MIF may be pathogenic in AKI and levels of plasma and urinary MIF may correlate with the progression and regression of AKI.

Correlation between Plasma Macrophage Migration Inhibitory Factor Levels and Long-Term Prognosis in Patients with Acute Myocardial Infarction Complicated with Diabetes.

Macrophage migration inhibitory factor (MIF), a widely expressed pleiotropic cytokine, is reportedly involved in several cardiovascular diseases, in addition to inflammatory diseases. Plasma MIF levels are elevated in the early phase of acute cardiac infarction. This study is aimed at investigating the correlation between plasma MIF levels and cardiac function and prognosis in patients with acute ST-segment elevation myocardial infarction (STEMI) with or without diabetes mellitus. Overall, 204 patients with STEMI who underwent emergency percutaneous coronary intervention were enrolled: 57 and 147 patients in the diabetes and nondiabetes STEMI groups, respectively. Sixty-five healthy people were selected as controls. Plasma MIF levels were measured at the time of diagnosis. Basic clinical data and echocardiographic findings within 72 h of admission were collected. Patients were followed up, and echocardiograms were reviewed at the 12-month follow-up. Plasma MIF levels were significantly higher in the diabetes and nondiabetes STEMI groups than in the control group and in patients with Killip grade ≥ II STEMI than in those with Killip grade I. Plasma MIF levels were negatively correlated with the left ventricular ejection fraction (LVEF) of myocardial infarction in patients with or without diabetes in the acute phase of infarction, whereas the left ventricular diastolic dysfunction (LVDD) was positively correlated. MIF levels in the nondiabetes STEMI group were positively correlated with N-terminal pro-b-type natriuretic peptide levels and were associated with LVEF and LVDD at the 12-month follow-up. The risk of adverse cardiovascular and cerebrovascular events was significantly higher in the MIF high-level group (≥52.7 ng/mL) than in the nondiabetes STEMI group 36 months after presentation. Thus, MIF levels in STEMI patients with or without diabetes can reflect acute cardiac function. In STEMI patients without diabetes, MIF levels can also indicate cardiac function and long-term prognosis at the 12-month follow-up.

Prognostic significance and dynamic change of plasma macrophage migration inhibitory factor in patients with acute ST-elevation myocardial infarction.

Macrophage migration inhibitory factor (MIF) has been reported as an inflammatory cytokine in many inflammatory diseases, including rheumatoid arthritis and ischemic diseases. However, dynamic changes of MIF within the first 24 hours on admission and potential prognostic significance following ST-elevation myocardial infarction (STEMI) have been little known. In this study, we examined the dynamic change of MIF level and its potential diagnostic and prognostic value after the onset of STEMI. Plasma MIF levels were evaluated in symptomatic subjects who received coronary angiogram with a median 27 months follow-up for the development of major adverse cardiovascular events (MACEs).Of all 993 subjects, patients with STEMI showed a significantly higher MIF levels than in patients with non-ST elevation acute coronary syndrome, stable angina, and normal coronary artery, respectively (P < .01). Plasma MIF levels elevated as early as 12 hours post-onset of STEMI and peaked rapidly within 24 hours, and remained elevated from about day 5 till day 9 during hospitalization. In multivariate analysis, MIF was associated with a decreased risk of MACEs occurrence in STEMI patients after adjustment for traditional cardiovascular risk factors [hazard ratio 0.81, (0.72-0.90), P < .001]. The ROC curve for MACEs was 0.72 (95% CI 0.62-0.80, P < .001) and 0.85 (95% CI 0.80-0.90, P < .001) using Framingham risk factors only and combined with MIF, individually.Measurement of MIF adds potential information for the early diagnosis of acute STEMI and significantly improves risk prediction of MACEs when added to a prognostic model with traditional Framingham risk factors.

Neutralization of macrophage migration inhibitory factor improves host survival after Clostridium difficile infection

Clostridium difficile is an important cause of nosocomial diarrhea in the western world. Toxins (A, B, and binary toxins) generated by C. difficile bacteria damage intestinal epithelial cells. Hallmarks of host response to C. difficile infection (CDI) include upregulation of inflammatory mediators and tissue infiltration by immune cells. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that is known to enhance the host immune response to infectious pathogens. Additionally, MIF can adversely impact host survival to numerous infections. The role of MIF in the pathogenesis of CDI remains poorly understood. Here, we show that patients with CDI had significantly higher circulating MIF compared to patients who had diarrhea but tested negative for C. difficile (non-CDI controls). Similarly, in a mouse model, C. difficile challenge significantly increased levels of plasma and tissue MIF. Antibody-mediated depletion of MIF decreased C. difficile-induced inflammatory responses, clinical disease, and mortality. Together, these results uncover a potential role for MIF in exacerbating CDI and suggest that use of anti-MIF antibodies may represent a therapeutic strategy to curb host inflammatory responses and improve disease outcomes in CDI.

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.

Association of Macrophage Migration Inhibitory Factor Polymorphisms with Total Plasma IgE Levels in Patients with Atopic Dermatitis in Korea.

The macrophage migration inhibitory factor (MIF) gene is located on human chromosome 22q11.2 and is linked to atopic phenotypes. Plasma MIF and log [total IgE] levels are significantly elevated in atopic dermatitis (AD) patients. The aim of this study was to evaluate the relationship between two MIF polymorphisms, −173 G to C and −794 CATT5–8, and total plasma IgE levels in AD patients in Korea. We performed PCR-RFLP analysis in 178 AD patients and 80 control subjects to determine whether MIF SNPs are associated with susceptibility to AD. Plasma total IgE and MIF levels were determined, and then logistic regression analyses were performed to determine the associations between a SNP or haplotype and plasma total IgE or MIF levels. The −173 G/C polymorphism, located in the MIF promoter, was significantly associated with AD; the odds ratios (ORs) for the CC homozygotes and GC heterozygotes were 9.3 and 2.5, respectively. The MIF C/5-CATT and the MIF C/7-CATT haplotypes were significantly associated with AD; the ORs for the MIF C/5-CATT and MIF C/7-CATT haplotypes were 9.7 and 4.5, respectively. Log [total IgE] levels were highly associated with the MIF −794 7-CATT polymorphism. Notably, the MIF C/7-CATT haplotype was associated with a decrease in plasma log [total IgE] levels in a gene dose-dependent manner. Although log [MIF] levels were not associated with the MIF polymorphisms, the frequencies of the MIF C/5-CATT haplotype-containing genotypes decreased in order of MIF levels. Our results demonstrate that MIF promoter polymorphisms in the −173 C allele and the MIF C/5-CATT and C/7-CATT haplotypes were significantly associated with an increased risk for AD. In particular, the −794 7-CATT locus and the MIF C/7-CATT haplotype were significantly associated with decreased total IgE levels in the plasma, suggesting that these polymorphisms might be a marker for intrinsic AD rather than extrinsic AD that shows high total IgE levels and presence of allergen-specific IgE.