High 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.

Correlation of Serum High-Sensitivity C-Reactive Protein, Homocysteine, and Macrophage Migration Inhibitory Factor Levels With Symptom Severity and Cognitive Function in Patients With Schizophrenia.

This trial analyzed high-sensitivity C-reactive protein (hs-CRP), homocysteine (Hcy), and macrophage migration inhibitory factor (MIF) level in serum and their correlation with symptom severity and cognitive function in patients with schizophrenia (SP). Sixty-eight SP patients were enrolled in the SP group, and 68 healthy volunteers were in the control (CN) group. Serum hs-CRP, Hcy, and MIF were measured, and symptom severity was assessed with the Positive and Negative Symptom Scale (PANSS). Cognitive function was determined with the MATRICS Consensus Cognitive Battery (MCCB). The SP group was divided into high PANSS score (PANSS ≥70 points) and low PANSS score (PANSS <70 points), or the mild cognitive dysfunction group and severe cognitive dysfunction group according to the median MCCB score. The correlation between serum hs-CRP, Hcy, and MIF levels and PANSS and MCCB scores in SP patients was examined by Pearson correlation analysis. SP patients had higher serum hs-CRP, Hcy, and MIF levels and showed higher PANSS scores and lower MCCB total score. Serum hs-CRP, Hcy, and MIF levels in the high PANSS group were higher than those in the low PANSS group and in the severe cognitive dysfunction group than in the mild cognitive dysfunction group. Serum hs-CRP, Hcy, and MIF levels in SP patients were positively correlated with PANSS total score and negatively correlated with MCCB total score. High serum hs-CRP, Hcy, and MIF levels in SP patients are correlated with symptom severity and cognitive dysfunction.

Macrophage migration inhibitory factor (MIF) and IgA anti CD74 antibodies in Indian patients with enthesitis-related arthritis category of Juvenile idiopathic arthritis.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in pathogenesis of ankylosing spondylitis (AS). CD 74 is the receptor for MIF and IgA antiCD74 autoantibodies have been described from different parts of the world in patients with AS. As enthesitis-related arthritis (ERA) is a form of juvenile spondyloarthropathy, we studied the serum and synovial fluid levels of MIF in ERA and looked for the IgA antiCD74 antibodies in patients with ERA in our population. Patients with JIA (ILAR classification) were studied. Serum MIF levels were measured by ELISA in 101 patients of ERA (synovial fluid also where available) and compared to 28 patients of other categories of JIA, 25 patients each of ankylosing spondylitis and rheumatoid arthritis, and 38 healthy controls. In addition, associationof MIF with disease activity was assessed. Ig A antiCD74 antibodies were measured in sera of ERA, AS and healthy controls. Median serum MIF levels were higher in ERA [2.50 (1.20-4.85) ng/ml] than in healthy controls [0.28 (0.16-0.48); p < 0.0001] and patients with RA [1.13 (0.44-2.45); p < 0.01] MIF levels in ERA were comparable to other categories of JIA [2.63 (1.70-4.05)] and patients with AS [3.62 (0.52-6.51)]. Synovial fluid MIF levels were higher than serum levels (p < 0.01). Serum MIF level had an association with the JSpADA score (r = 0.29, p < 0.01). Serum MIF levels had no association with presence of inflammatory markers, enthesitis, inflammatory back pain or sacroiliitis. IgA AntiCD74 antibody was positive only in 3/88 (3.41%) of ERA patients and was not detected in any patients of AS or healthy controls. Patients with ERA have high MIF levels that show modest correlation with disease activity. Higher synovial fluid MIF levelssuggest that it may play a role in synovitis seen in ERA. IgA antiCD74 antibodies are rarely seen in ERA.

AN INDICATOR OF ACTIVE PULMONARY TUBERCULOSIS IN SERUM AS SERUM MACROPHAGE MIGRATION INHIBITORY FACTOR

Background: It has been demonstrated that the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF), which has chemokine-like properties, is a key player in a number of acute and long-term inflammatory disorders. However, nothing is known regarding the application of MIF as an inflammatory pathway marker in tuberculosis patients. The purpose of this study was to look at the relationship between MIF and IFN- and TNF-( relationship of MIF with IFN and TNF) in active pulmonary tuberculosis after anti-tuberculosis medication. Methods: By using cytokine-specific ELISA, the serum levels of MIF, TNF, and IFN were assessed in 40 patients with APTB at four different times: at baseline, 3, 5, and 7 months after starting anti-tuberculosis medication. Additionally, we assessed the serum levels of MIF, TNF, and IFN in 40 healthy controls. Results: Prior to the procedure, MIF serum levels were substantially higher (P&lt;0.04) in patients with APTB than in normal subjects, and high MIF levels (13.0 ng/mL) were linked to high TNF- α levels (449.6 pg/mL). Following 3, 5, and 7 months of treatment, MIF levels were considerably lowered (P&lt;0.02), with changes in TNF-α and IFNβ-serum levels. MIF levels and the paired TNF- level had a positive correlation at baseline (r=0.1102, P=0.0315) and after 7 months of treatment (r=0.09568, P=0.0363). Conclusion: After anti-tuberculosis therapy, a decrease in MIF serum levels in APTB patients might enhance the host immune system's defence against Mycobacterium tuberculosis infection. Therefore, serum MIF levels may serve as a helpful measure for evaluating the efficacy of medication in APTB patients.

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).&#x0D; 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 &lt; 2501 pg/ml (first group, n = 60) and &gt; 2501 pg/ml (second group, n = 60).&#x0D; 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 &gt; 2694 pg/ml (sensitivity 69.2 %, specificity 71.4 %, AUC = 0.714; 95 % CI 0.509 — 0.870; p = 0.0375) and LV dysfunction &gt; 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.&#x0D; 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.

Autophagy inhibition in breast cancer cells induces ROS-mediated MIF expression and M1 macrophage polarization

Autophagy can function as a survival mechanism for cancer cells and therefore, its inhibition is currently being explored as a therapy for different cancer types. For breast cancer, triple negative breast cancer (TNBC) is the subtype most sensitive to the inhibition of autophagy; but its inhibition has also been shown to promote ROS-dependent secretion of macrophage migration inhibitory factor (MIF), a pro-tumorigenic cytokine. In this work, we explore the role of MIF in breast cancer, the mechanism by which autophagy inhibition promotes MIF secretion and its effects on neighboring cancer cell signaling and macrophage polarization. We analyzed MIF mRNA expression levels in tumors from breast cancer patients from different subtypes and found that Luminal B, HER2 and Basal subtypes, which are associated to high proliferation, displayed high MIF levels. However, MIF expression had no prognostic relevance in any breast cancer subtype. In addition, we found that autophagy inhibition in 66cl4 TNBC cells increased intracellular Reactive Oxygen Species (ROS) levels, which increased MIF expression and secretion. MIF secreted from 66cl4 TNBC cells induced the activation of MIF-regulated pathways in syngeneic cell lines, increasing Akt phosphorylation in 4T1 cells and ERK phosphorylation in 67NR cells. Regarding MIF/ chemokine receptors, higher levels of CD74 and CXCR2 were found in TNBC tumor cell lines when compared to non-tumorigenic cells and CXCR7 was elevated in the highly metastatic 4T1 cell line. Finally, secreted MIF from autophagy deficient 66cl4 cells induced macrophage polarization towards the M1 subtype. Together, our results indicate an important role for the inhibition of autophagy in the regulation of ROS-mediated MIF gene expression and secretion, with paracrine effects on cancer cell signaling and pro-inflammatory repercussions in macrophage M1 polarization. This data should be considered when considering the inhibition of autophagy as a therapy for different types of cancer.

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)

Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer

Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some cancers via stabilization with HSP90-associated chaperones. Here, we show that MIF stabilization is tumor-specific in an acute colitis-associated colorectal cancer (CRC) mouse model, leading to tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC tumor growth. Further, we define a dual role for MIF in CRC tumor progression. Mif deletion protects mice from inflammation-associated tumor initiation, confirming the action of MIF on host inflammatory pathways; however, macrophage recruitment, neoangiogenesis, and proliferative responses are reduced in Mif-deficient tumors once the tumors are established. Thus, during neoplastic transformation, the function of MIF switches from a proinflammatory cytokine to an angiogenesis promoting factor within our experimental model. Mechanistically, Mif-containing tumor cells regulate angiogenic gene expression via a MIF/CD74/MAPK axis in vitro. Clinical correlation studies of CRC patients show the shortest overall survival for patients with high MIF levels in combination with CD74 expression. Pharmacological inhibition of HSP90 to reduce MIF levels decreased tumor growth in vivo, and selectively reduced the growth of organoids derived from murine and human tumors without affecting organoids derived from healthy epithelial cells. Therefore, novel, clinically relevant Hsp90 inhibitors provide therapeutic selectivity by interfering with tumorigenic MIF in tumor epithelial cells but not in normal cells. Furthermore, Mif-depleted colonic tumor organoids showed growth defects compared to wild-type organoids and were less susceptible toward HSP90 inhibitor treatment. Our data support that tumor-specific stabilization of MIF promotes CRC progression and allows MIF to become a potential and selective therapeutic target in CRC.

Peripheral blood and tissue assessment highlights differential tumor-circulatory gradients of IL2 and MIF with prognostic significance in resectable pancreatic ductal adenocarcinoma

ABSTRACT Various reports have pointed out the potential of cytokines as diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma (PDA). Nonetheless, the evidence is contradictory and the role of chronic inflammation and relationship between circulatory and corresponding tumoral cytokine levels remain elusive. Utilizing a broad array of cytokines, we identified two opposing parameters: serum levels of interleukin 2 (IL2) and macrophage migration inhibitory factor (MIF) are diagnostic and prognostic factors. While low IL2 levels are associated with PDA, they also relate to a favorable prognosis of patients. In contrast, high MIF levels are associated with PDA and simultaneously related to an unfavorable outcome. MIF levels are associated with the intratumoral density of M2 macrophages (CD163+). Focusing on the tumor-to-serum gradient, we unveiled a different pattern of compartmental cytokine expression between IL2 and MIF. Our findings indicate that an extra-tumoral source of IL2 exists in PDA patients leading to increased detectability in the circulatory system. In case of MIF, the tumor microenvironment is presumably the main site of production and thereby reflected by serum measurements. Taken together, our study describes IL2 and MIF levels as biomarker candidates for diagnosis and prognosis of PDA, highlighting the need for compartmental cytokine analyses. From the perspective of tumor immunobiology, we identify multiple inflammatory states (proposed as types I–III) and see that systemic chronic dysregulation, independent of tumor microenvironment, can be measured and is a possible tool for stratification. Thus, direct correlation of local cytokine levels to peripheral blood levels needs to be regarded with caution.

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.

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.

The relationship of macrophage migration inhibitory factor with clinical and anamnestic parameters in patients with ST-segment elevation myocardial infarction

Objective — to investigate the association between levels of the macrophage migration inhibitory factor (MIF) and the clinical and anamnestic parameters in patients with ST segment elevation myocardial infarction (STEMI) and to determine the factors, affecting this relationship.Materials and methods. The study involved 73 patients with previous confirmed STEMI and successful recovery of blood flow (TIMI-III). The mean patients’ age was (58.37 ± 10.34) years. Clinical, anamnestic and biochemical indicators were determined. The level of MIF was studied using the enzyme linked immunoassay method (RayBio® Human MIF ELISA KIT, USA). The general group of patients was divided by the median MIF level: the first group consisted of patients with low or moderate MIF (≤ 2582.80 ng/ml), n = 36, the second group consisted pf patients with high levels of this cytokine (&gt; 2582.80 ng/ml), n = 37. Mono- and multivariate regression analysis was carried out to identify factors, that mostly significantly affected the MIF levels.Results and discussion. The comparison of median values of the MIF levels in STEMI patients revealed the significant increase in MIF levels vs the control group (2582.80 [1308.40—4122.20] and (573.75 [397.80—1016.75] ng/ml, p &lt; 0.001), that confirmed activation of the MIF formation because of the index event. Positive correlation was determined between the MIF levels, levels of troponin I (r = 0.33; p = 0.045) and blood leukocytes (r = 0.36; p = 0.039). Anterior myocardial infarction (p = 0.047) and injury of left anterior descending artery (p = 0.016) were detected more frequently in the group of patients with high MIF levels, that indicates its directly connection with the size of the myocardial infarction in combination with significantly higher troponin level. Multivariate and univariate logistic analysis showed the reliable independent association between the anterior localization of the MI and the elevated MIF level (OR = 0.2282, 95 % CI [0.1035—0.7680], p = 0.0133), as well as the presence of stable angina to the index event and the lower level of cytokine (OR = 0.2318, 95 % CI [0.0637—0.8438], p = 0.0266).Conclusions. The macrophage migration inhibitory factor at STEMI is involved in the processes of inflammation and necrosis, its increase indicates the direct relationship with the myocardial infarction extension. The presence of stable angina prior the myocardial infarction promotes the pre-conditioning effect and a lower degree of damage, and proportionally lower MIF levels.

Macrophage migration inhibitory factor is a novel prognostic marker for human oral squamous cell carcinoma

Macrophage migration inhibitory factor (MIF) is considered a pro-tumour factor. However, its clinical relevance in oral squamous cell carcinoma (OSCC) remains unclear. The objective of this study was to investigate the expression of MIF and its receptor CD74 in OSCC tissues, and to study the function of MIF in OSCC cells. Tissues of 90 patients with OSCC from the School of Stomatology, China Medical University were collected, and immunohistochemical staining and quantitative reverse transcription polymerase chain reaction were performed for MIF and CD74. The possible correlations between MIF and CD74 and clinical characteristics were analysed. The Kaplan-Meier analysis was used to determine the survival rates of patients. In addition, the proliferation and invasion of OSCC cells were evaluated after transfection with siRNA against MIF. MIF and CD74 levels were significantly higher in tissues of patients with OSCC than in control tissues. Moreover, MIF levels in patients with OSCC were significantly associated with cell differentiation and TNM classification. MIF expression was closely related to CD74 expression. Kaplan-Meier analysis indicated that OSCC patients with high MIF levels showed reduced overall survival and recurrenc-free survival. Furthermore, MIF expression promoted proliferation and invasion of OSCC cells. Collectively, our results reveal that MIF expression is a significant independent prognostic factor for patients with OSCC and may be a novel prognostic marker for OSCC.

Predictive potential of macrophage migration inhibitory factor (MIF) in patients with heart failure with preserved ejection fraction (HFpEF)

BackgroundPrognostication in heart failure with preserved ejection fraction (HFpEF) is challenging and novel biomarkers are urgently needed. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays a crucial role in cardiovascular and various inflammatory diseases. Whether MIF is involved in HFpEF is unknown.Methods and resultsSixty-two patients with HFpEF were enrolled and followed up for 180 days. MIF plasma levels as well as natriuretic peptide (NP) levels were assessed. High MIF levels significantly predicted the combined end-point of all-cause death or hospitalization at 180 days in the univariate analysis (HR 2.41, 95% CI 1.12–5.19, p = 0.025) and after adjustment for relevant covariates in a Cox proportional hazard regression model (HR 2.35, 95% CI 1.05–5.27, p = 0.0374). Furthermore, MIF levels above the median were associated with higher pulmonary artery systolic pressure (PASP) as assessed by echocardiography (PASP 31 mmHg vs 48 mmHg in the low- and high-MIF group, respectively, p = 0.017). NPs significantly correlated with MIF in HFpEF patients (BNP p = 0.011; r = 0.32; NT-proBNP p = 0.027; r = 0.28).ConclusionMIF was associated with clinical outcomes and might be involved in the pathophysiology of pulmonary hypertension in patients with HFpEF. These first data on MIF in HFpEF should stimulate further research to elucidate the role of this cytokine in heart failure.Trial registration NCT03232671

Effects of probiotics supplementation on macrophage migration inhibitory factor and clinical laboratory feature of polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is a set of reproductive and metabolic symptoms associated with an imbalance of reproductive hormones in women. Macrophage migration inhibitory factor (MIF) is an inflammatory adipocytokine associated with metabolic disorders. Probiotics probably has influence on metabolic and inflammatory conditions. We aimed by this study, for the first time, to evaluate the impact of probiotic supplementation on MIF values, clinical and laboratory feature of PCOS. Furthermore, we aimed to explore the power of MIF for diagnosis PCOS. MethodsSixty women diagnosed with PCOS were selected in this single-blinded clinical trial and 40 healthy control women. Participants received probiotic supplements for 12-week. Clinical and laboratory measures were evaluated at baseline and after 12weeks of intervention. High sensitivity C-reactive protein (hs-CRP) and MIF levels were assessed using an enzyme-linked immunosorbent assay (ELISA). ResultsProbiotic supplementation improved clinical, hormonal, and inflammatory biomarkers in women with PCOS. Additionally in PCOS group, logistic regression analysis revealed that MIF and HOMA-IR were independent predictors of probiotic response with odds ratios of 1.641 and 0.335, respectively. Regarding inflammatory biomarkers, hs-CRP and MIF, its value increased in PCOS group compared to healthy group. Receiver operating characteristic curve (ROC) analysis revealed that, area under the curve (AUC) for the MIF was 0.981 (95% CI=0.902–0.898) with sensitivity=90.2%, specificity=89.8% and the cutoff values (19.7). Interestingly, the power of MIF was more sensitive and specific than hs-CRP for diagnosis of PCOS. Thus MIF could be a useful diagnostic inflammatory biomarker discriminating PCOS from healthy controls. Moreover in PCOS group stepwise multiple linear regression analysis, detected that HOMA-IR, neutrophil count, hs-CRP and fat mass index (FMI) were main predictors of MIF levels among other clinical and laboratory biomarkers. ConclusionRegarding the effects of probiotic supplementation on inflammatory and metabolic disorders; our novel findings explored a favorable effect of probiotic supplementation on inflammatory biomarkers; clinical, laboratory features of PCOS, and MIF levels. Furthermore, probiotic could be used for treatment of PCOS and its associated morbidity.

Role of MIF/CD74 signaling pathway in the development of pleural mesothelioma.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine implicated in acute and chronic inflammatory diseases. MIF is overexpressed in various tumors. It displays a number of functions that provide a direct link between the process of inflammation and tumor growth. Our group recently identified the MIF-receptor CD74 as an independent prognostic factor for overall survival in patients with malignant pleural mesothelioma.In the present study, we compared the levels of expression of MIF and CD74 in different human mesothelioma cell lines and investigated their physiopathological functions in vitro and in vivo.Human mesothelioma cells expressed more CD74 and secreted less MIF than non tumoral MeT5A cells, suggesting a higher sensitivity to MIF. In mesothelioma cells, high MIF levels were associated with a high multiplication rate of cells. In vitro, reduction of MIF or CD74 levels in both mesothelioma cell lines showed that the MIF/CD74 signaling pathway promoted tumor cell proliferation and protected MPM cells from apoptosis. Finally, mesothelioma cell lines expressing high CD74 levels had a low tumorigenic potential after xenogeneic implantation in athymic nude mice.All these data highlight the complexity of the MIF/CD74 signaling pathway in the development of mesothelioma.

MIF reflects tissue damage rather than inflammation in post-cardiac arrest syndrome in a real life cohort

IntroductionFollowing successful resuscitation from cardiac arrest (CA), neurological impairment and other types of organ dysfunction cause significant morbidity and mortality—a condition termed post-cardiac arrest syndrome. Whole-body ischemia/reperfusion with oxygen debt activates immunologic and coagulation pathways increasing the risk of multiple organ failure and infection. We here examined the role of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) in post-cardiac arrest syndrome. MethodsMIF plasma levels of n=16 patients with return of spontaneous circulation (ROSC) after CA were assessed with a previously validated method and compared to markers of systemic inflammation and cellular damage. ICU patients without former CA and healthy volunteers served as controls. ResultsMIF levels in patients after ROSC were higher compared to those in healthy volunteers and ICU patients without CA. Kaplan–Meyer analysis revealed a distinctly elevated mortality since day one that further increased towards an elevated 60-days-mortality in patients with high plasma MIF. ROC curve identified plasma MIF as a predictor for mortality in patients after CA. Correlation with inflammatory parameters revealed that high MIF levels did not mirror post CA inflammatory syndrome, but distinctive cellular damage after ROSC as there were strong correlations with markers of cellular damage like LDH and GOT/GPT. ConclusionHigh MIF levels were associated with elevated 60-days-mortality and high MIF predicted mortality after CA. We found a close relation between circulating MIF levels and cellular damage, but not with an inflammatory syndrome.

O-065 Macrophage Migration Inhibitory Factor Balances Neonatal Innate Immune Responses

Background The vulnerability to infection observed in newborns is associated with a limited ability to mount efficient immune responses. Elevated circulating levels of anti-inflammatory mediators (adenosine, prostaglandins,...) reduce production of pro-inflammatory cytokines by newborn monocytes upon microbial challenge. We hypothesised that macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine constitutively expressed in blood and immune cells, counter-balances the anti-inflammatory milieu of newborns. Methods MIF plasma levels were measured by ELISA in 200 healthy subjects, from birth to adulthood. Cord blood monocytes from term newborns were transfected with MIF siRNA, or were incubated with the MIF antagonist ISO-1, recombinant MIF, adenosine and prostaglandin E2 (PGE2) and then stimulated with endotoxin, bacterial lipopeptide, Escherichia coli and Group B Streptococcus (GBS). Intracellular proteins and cell-culture supernatants were collected to quantify MAPK phosphorylation by Western blot and cytokines by ELISA/Luminex. Results Circulating MIF levels were 10-fold higher in newborns than adults, and decreased during infancy. Newborn monocytes expressed high MIF levels, and released MIF upon stimulation with Escherichia coli and GBS. Inhibition of MIF expression with MIF siRNA or MIF activity with ISO-1 reduced 1.5–5.7-fold microbial product-induced secretion of pro-inflammatory (TNF, IL-1β, IL-6, IL-8, IL-12p40, IL-12p70, IL-23) and anti-inflammatory (IL-10, IL-20, IL-27) cytokines and phosphorylation of p38 and ERK1/2 MAPKs. Recombinant MIF counter-regulated adenosine and PGE2-mediated inhibition of TNF production in Escherichia coli -stimulated newborn monocytes. Conclusions MIF expression is developmentally regulated, with strikingly elevated levels in newborns compared to adults. High MIF levels at birth may act to balance pro/anti-inflammatory immune responses in newborns.

Macrophage migration inhibitory factor engages PI3K/Akt signalling and is a prognostic factor in metastatic melanoma.

BackgroundMacrophage migration inhibitory factor (MIF) is a widely expressed cytokine involved in a variety of cellular processes including cell cycle regulation and the control of proliferation. Overexpression of MIF has been reported in a number of cancer types and it has previously been shown that MIF is upregulated in melanocytic tumours with the highest expression levels occurring in malignant melanoma. However, the clinical significance of high MIF expression in melanoma has not been reported.MethodsMIF expression was depleted in human melanoma cell lines using siRNA-mediated gene knockdown and effects monitored using in vitro assays of proliferation, cell cycle, apoptosis, clonogenicity and Akt signalling. In silico analyses of expression microarray data were used to correlate MIF expression levels in melanoma tumours with overall patient survival using a univariate Cox regression model.ResultsKnockdown of MIF significantly decreased proliferation, increased apoptosis and decreased anchorage-independent growth. Effects were associated with reduced numbers of cells entering S phase concomitant with decreased cyclin D1 and CDK4 expression, increased p27 expression and decreased Akt phosphorylation. Analysis of clinical outcome data showed that MIF expression levels in primary melanoma were not associated with outcome (HR = 1.091, p = 0.892) whereas higher levels of MIF in metastatic lesions were significantly associated with faster disease progression (HR = 2.946, p = 0.003 and HR = 4.600, p = 0.004, respectively in two independent studies).ConclusionsOur in vitro analyses show that MIF functions upstream of the PI3K/Akt pathway in human melanoma cell lines. Moreover, depletion of MIF inhibited melanoma proliferation, viability and clonogenic capacity. Clinically, high MIF levels in metastatic melanoma were found to be associated with faster disease recurrence. These findings support the clinical significance of MIF signalling in melanoma and provide a strong rationale for both targeting and monitoring MIF expression in clinical melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-630) contains supplementary material, which is available to authorized users.

High levels of serum macrophage migration inhibitory factor and interleukin 10 are associated with a rapidly fatal outcome in patients with severe sepsis

The aim of this study was to delineate the association between high macrophage migration inhibitory factor (MIF) and interleukin 10 (IL-10) levels in the early phase of sepsis and rapidly fatal outcome. One hundred and fifty-three adult subjects with the main diagnosis of severe sepsis (including septic shock) admitted directly from the emergency department of two tertiary medical centers and one regional teaching hospital between January 2009 and December 2011, were included prospectively. MIF and IL-10 levels were measured and outcomes were analyzed by Cox regression analysis according to the following outcomes: rapidly fatal outcome (RFO, death within 48 h), late fatal outcome (LFO, death between 48 h and 28 days), and survival at 28 days. Among the three outcome groups, IL-10 levels were significantly higher in the RFO group (p < 0.001) and no significant differences were seen between the LFO and survivor groups. After Cox regression analysis, each incremental elevation of 1000 pg/ml in both IL-10 and MIF was independently associated with RFO in patients with severe sepsis. Each incremental elevation of 1000 pg/ml in IL-10 increased the RFO risk by a factor of 1.312 (95% confidence interval 1.094-1.575; p=0.003); this was the most significant factor leading to RFO in patients with severe sepsis. Patients with RFO exhibited simultaneously high MIF and IL-10 levels in the early phase of severe sepsis. Incremental increases in both IL-10 and MIF levels were associated with RFO in this patient group, and of the two, IL-10 was the most significant factor linked to RFO.