Serum Macrophage Migration Inhibitory Factor Levels Research Articles

MIF and CD74 as Emerging Biomarkers for Immune Checkpoint Blockade Therapy.

Immune checkpoint blockade (ICB) therapy is used to treat a wide range of cancers; however, some patients are at risk of developing treatment resistance and/or immune-related adverse events (irAEs). Thus, there is a great need for the identification of reliable predictive biomarkers for response and toxicity. The cytokine MIF (macrophage migration inhibitory factor) and its cognate receptor CD74 are intimately connected with cancer progression and have previously been proposed as prognostic biomarkers for patient outcome in various cancers, including solid tumors such as malignant melanoma. Here, we assess their potential as predictive biomarkers for response to ICB therapy and irAE development. We provide a brief overview of their function and roles in the context of cancer and autoimmune disease. We also review the evidence showing that MIF and CD74 may be of use as predictive biomarkers of patient response to ICB therapy and irAE development. We also highlight that careful consideration is required when assessing the potential of serum MIF levels as a biomarker due to its reported circadian expression in human plasma. Finally, we suggest future directions for the establishment of MIF and CD74 as predictive biomarkers for ICB therapy and irAE development to guide further research in this field.

The Combination of circEPSTI1 and MIF Offers Diagnostic Value for Endometrial Cancer.

Circular RNAs (circRNAs) exhibit unique patterns of expression and high levels of stability in patient plasma samples such that they represent ideal non-invasive biomarkers that can be leveraged to detect a wide array of diseases including endometrial cancer (EC). This study was designed to identify circRNAs with potential diagnostic utility in serum samples from EC patients while also evaluating the utility of macrophage migration inhibitory factor (MIF) as a biomarker when screening for this form of cancer in the clinic. Levels of circEPSTI1 and MIF were assessed in the plasma of EC patients and healthy subjects (n=186 each) through qPCR and ELISAs. The diagnostic utility of these biomarkers was assessed with receiver operating characteristic curve (ROC) analyses. Relative to healthy subjects, EC patient serum contained significantly elevated circEPSTI1 and MIF. An association was noted between circEPSTI1 expression in stages, histologic grade, and residual tumor. ROC curves confirmed that serum circEPSTI1 levels distinguished between controls and patients with EC with an Area of 0.835 and serum MIF levels distinguished between controls and patients with EC with an Area of 0.6646. When instead diagnosing patients based on the combination of MIF and circEPSTI1, the Area further rose to 0.8604. Assessing the combination of circEPSTI1 and MIF may be a viable approach to reliably diagnosing EC.

Lack of clinical utility of serum macrophage migration inhibitory factor (MIF) for monitoring therapy response and estimating prognosis in advanced lung cancer.

Lung cancer is a major burden to global health and is still among the most frequent and most lethal malignant diseases. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in a variety of processes including tumorigenesis, formation of a tumor microenvironment and metastasis. It is therefore a potential prognostic biomarker in malignant diseases. In this study, we investigated the applicability of MIF in serum samples as a biomarker in lung cancer. In a retrospective approach, we analyzed the sera of 79 patients with non-small-cell lung cancer (NSCLC) and 14 patients with small-cell lung cancer (SCLC) before the start of chemotherapy, as well as before the second and third chemotherapy cycle, respectively. Serum MIF levels were measured using a sandwich immunoassay with a sulfo-tag-labelled detection antibody, while pro-gastrin releasing peptide (proGRP) levels were determined with an enzyme-linked immunosorbent assay. No difference in serum MIF levels between responders and non-responders to chemotherapy was observed at all time points, while proGRP levels were significantly lower in responders before the second chemotherapy cycle (p = 0.012). No differences in biomarker levels depending on the histopathological classification of NSCLC patients was found. Moreover, in ROC curve analyses MIF was not able to distinguish between responders and non-responders to therapy. proGRP could differentiate between responders and non-responders before the second chemotherapy cycle (p = 0.015) with sensitivities of 43% at 90% and 95% specificity, respectively. Likewise, proGRP yielded significantly longer survival times of patients with low proGRP concentrations before the second chemotherapy cycle (p = 0.015) in Kaplan-Meier analyses, yet MIF showed no significant differences in survival times at all time points. Comparison with the biomarkers CEA and CYFRA 21-1 in the same cohort showed that these established biomarkers clearly performed superior to MIF and proGRP. From the present results, there is no indication that serum MIF may serve as a biomarker in prognosis and monitoring of response to therapy in lung cancer. Limitations of this study include its retrospective design, the inclusion of a larger NSCLC and a smaller SCLC subgroup, the classical chemotherapeutic treatment, the use of a non-diagnostic immunoassay (RUO-test) for MIF measurement and the lack of a validation cohort. Strengths of the study are its highly standardized procedures concerning sample collection, preanalytic treatment, measurements and quality control of the laboratory assays.

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.

Predictive value of serum alkaline phosphatase, tumor-specific growth factor, and macrophage migration inhibitory factor for the efficacy of immunotargeted therapy in osteosarcoma patients.

To assess the predictive value of serum alkaline phosphatase (ALP), tumor-specific growth factor (TSGF), and macrophage migration inhibitory factor (MIF) for the efficacy of combined immunosuppressive and targeted therapy in osteosarcoma (OS). We retrospectively analyzed clinical data from 161 OS patients treated at Xi'an Honghui Hospital from October 2020 to October 2022. Patients received 12 weeks of therapy with interferon-α (IFN-α) and bevacizumab. Serum levels of ALP, TSGF, and MIF were measured before and after treatment. Based on treatment efficacy, patients were categorized into effective and ineffective groups. Both univariate and logistic regression analyses were utilized to evaluate the influence of these biomarkers on therapy outcomes. A significant reduction in serum ALP, TSGF, and MIF levels post-treatment was found (all P<0.001). Higher pre-treatment levels of these biomarkers were associated with less effective outcomes (P<0.001). Pre-treatment levels of ALP, TSGF, and MIF are significant independent predictors of response to immunotargeted therapy in OS patients, suggesting their potential role in guiding treatment strategies.

Macrophage migration inhibitory factor: A noval biomarker upregulates in myasthenia gravis and correlates with disease severity and relapse

ObjectiveTo explore the relationship between macrophage migration inhibitory factor (MIF) and disease severity and relapse in patients with myasthenia gravis (MG). Methods145 MG patients including 79 new-onset patients, 30 remission patients and 36 relapse patients were enrolled in this study. The detailed characteristics of all enrolled MG patients were routinely recorded, including gender, age, type, MGFA classification, antibody, thymic status, clinical score, treatment, MGFA-PIS and B cell subsets (memory B cells, plasmablast cells and plasma cells) detected by flow cytometry. Serum MIF levels were measured by enzyme-linked immunosorbent assay (ELISA) kit. The correlation of MIF levels with clinical subtypes, disease severity and B cell subsets were investigated. Moreover, logistic regression analysis was applied to assess the factors affecting relapse of generalized MG (GMG). ResultsSerum MIF levels were higher in new-onset MG patients than those in controls and were positively associated with QMG score, MGFA classification and memory B cells. Subgroup analysis revealed that MIF levels were increased in GMG patients than in ocular MG (OMG), as well as elevated in MGFA III/IV compared with MGFA I/II. With the remission of the disease, the expression of serum MIF decreased. The multivariate logistic regression models indicated that high MIF and thymoma was a risk factor for relapse of GMG, and rituximab could prevent disease relapse. ConclusionsMIF can be used as a novel biomarker to reflect disease severity and predict disease relapse in MG patients.

Serum macrophage migration inhibitory factor levels predict brain atrophy in people with primary progressive multiple sclerosis

Background: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). Objective: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. Methods: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. Results: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = −0.113%, 95% confidence interval (CI): −0.204% to −0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. Conclusions: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect.

Retrospective study on the correlation between serum MIF level and the condition and prognosis of patients with traumatic head injury.

This study aimed to investigate the correlation between serum levels of macrophage migration inhibitory factor (MIF) and the condition and prognosis of patients with traumatic brain injury (TBI). A retrospective study design was used, and the clinical data of 131 TBI patients from February 2019 to January 2022 were analyzed. Patients were divided into mild (13-15 points), moderate (9-12 points), or severe (3-8 points) groups according to their Glasgow Coma Scale (GCS) score after admission. The serum levels of BDNF, MIF, and MBP in the three groups were compared, and their correlation with the severity of TBI was analyzed. Patients were then separated into a good prognosis group (4-5 points) and a poor prognosis group (≤3 points) based on their Glasgow Prognostic Score (GOS) after 6 months of follow-up. The predictive power of serum indexes and combined detection on prognosis was analyzed. Patients were classified into a mild group (n = 63), moderate group (n = 47), and severe group (n = 21) based on their GCS, with a significant difference noted in serum levels of MIF, MBP, and BDNF among patients with different degrees of severity (all P < 0.001). The MIF, MBP, and BDNF levels were lower in the mild group compared to the moderate (all P < 0.001) and severe group (all P < 0.001). Additionally, the MIF and BDNF levels in the moderate group were lower compared to the severe group (P = 0.011, P = 0.002). Patients with mild severity had lower serum MIF, MBP, and BDNF levels than those with other degrees, and these indexes were positively correlated with the severity of TBI (all P < 0.001, r = 0.62, r = 0.48, r = 0.58). Based on the GOS, patients were divided into a good prognosis group (n = 107) and a poor prognosis group (n = 24), with the levels of MIF, MBP, and BDNF in the good prognosis group being significantly lower than those in the poor prognosis group (P < 0.001, P = 0.007, P = 0.003). The area under the curve (AUC) of MIF was higher than that of MBP and BDNF in predicting the prognosis of TBI patients; however, the statistical differences were not significant (MIF vs. MBP, P = 0.239; MIF vs. BDNF, P = 0.211; BDNF vs. MBP, P = 0.899). The center line has a large displacement, CT annular cisterna compression, increased white blood cell count, MBP and BDNF were risk factors for prognosis in TBI patients (P = 0.005, P = 0.001, P = 0.005, P = 0.033, P = 0.044). The serum levels of MIF, MBP, and BDNF in TBI patients were positively correlated with the severity of the disease, and MBP, BDNF levels had predictive value in determining patient prognosis.

15-deoxy-Δ12,14-prostaglandin J2 relieved acute liver injury by inhibiting macrophage migration inhibitory factor expression via PPARγ in hepatocyte.

15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) exhibited potential to alleviate liver inflammation in chronic injury but was less studied in acute injury. Acute liver injury was associated with elevated macrophage migration inhibitory factor (MIF) levels in damaged hepatocytes. This study aimed to investigate the regulatory mechanism of hepatocyte-derived MIF by 15d-PGJ2 and its subsequent impact on acute liver injury. In vivo, mouse models were established by carbon tetrachloride (CCl4) intraperitoneal injection, with or without 15d-PGJ2 administration. 15d-PGJ2 treatment reduced the necrotic areas induced by CCl4. In the same mouse model constructed using enhanced green fluorescent protein (EGFP)-labeled bone marrow (BM) chimeric mice, 15d-PGJ2 reduced CCl4 induced BM-derived macrophage (BMM, EGFP+F4/80+) infiltration and inflammatory cytokine expression. Additionally, 15d-PGJ2 down-regulated liver and serum MIF levels; liver MIF expression was positively correlated with BMM percentage and inflammatory cytokine expression. In vitro, 15d-PGJ2 inhibited Mif expression in hepatocytes. In primary hepatocytes, reactive oxygen species inhibitor (NAC) showed no effect on MIF inhibition by 15d-PGJ2; PPARγ inhibitor (GW9662) abolished 15d-PGJ2 suppressed MIF expression and antagonists (troglitazone, ciglitazone) mimicked its function. In Pparg silenced AML12 cells, the suppression of MIF by 15d-PGJ2 was weakened; 15d-PGJ2 promoted PPARγ activation in AML 12 cells and primary hepatocytes. Furthermore, the conditioned medium of recombinant MIF- and lipopolysaccharide-treated AML12 respectively promoted BMM migration and inflammatory cytokine expression. Conditioned medium of 15d-PGJ2- or siMif-treated injured AML12 suppressed these effects. Collectively, 15d-PGJ2 activated PPARγ to suppress MIF expression in injured hepatocytes, reducing BMM infiltration and pro-inflammatory activation, ultimately alleviating acute liver injury.

Haplotypes of [-794(CATT)5-8 /-173G>C] MIF gene polymorphisms and its soluble levels in cutaneous squamous cell carcinoma in western Mexican population.

Some cytokines are strongly implicated in the development of squamous cell carcinoma (SCC) such as the Macrophage migration inhibitory factor (MIF). The haplotype -794 (CATT)5-8 /-173G>C in MIF gene polymorphisms has been associated with some types of cancer. The aim of this study is to establish the possible association between the presence of this haplotype in the MIF gene and its subsequent soluble levels with the susceptibility of SCC in western Mexican population. This study included 175 SCC patients and 175 age-sex-matched individuals as a reference group (RG) from western Mexico. Genomic DNA was extracted from peripheral blood leukocytes. Polymorphisms were genotyped by endpoint PCR and PCR-RFLP, and the determination of MIF serum levels was measured by ELISA. Clinical characteristics were evaluated by a group of dermatologists. Analysis of [-794(CATT)5-8 /-173G>C] MIF gene polymorphisms showed that the 5C (OR = 2.7, p = 0.02) and the 7G (OR = 3.39, p < 0.01) haplotypes are associated with susceptibility in SCC. MIF soluble levels in SCC patients showed a median of 13.93 ng/mL, whereas the reference group showed 6.000 ng/mL. Our findings suggest that 5C and 7G [-794(CATT)5-8 /-173G>C] MIF gene haplotypes are associated with susceptibility to SCC and that SCC patients present increased soluble levels of MIF.

Increasing Levels of Macrophage Migration Inhibitory Factor in COVID-19 Infection and Its Pathophysiological Role; Cut-off Value Determination Might Be Clinically Misleading

Background: The serious outbreak of coronavirus disease 2019 (COVID-19) has provoked deep concern throughout the world. The pathophysiologic network leading to severe conditions has still unsolved gaps. Considered a pleiotropic, multifaceted cytokine, macrophage migration inhibitory factor (MIF) has distinct functions, which seem to stand at the edge of distinct known mechanisms involving in COVID-19 pathogenesis. Additionally, MIF is a key mediator of acute respiratory distress syndrome and lung injury. Objectives: The current study aimed to evaluate the serum levels of MIF in COVID-19 patients, particularly in severe cases. Methods: This case control study was performed on the sera of 60 randomly selected COVID-19 patients as case group and 30 randomly selected healthy individuals as control group during November 2020 till April 2021 at Mashhad University of Medical Sciences. The case group included 30 outpatients with mild disease and 30 hospitalized severe subjects. A commercial enzyme-linked immunosorbent assay was utilized to measure serum MIF. Data were analyzed using SPSS version 16 with student t-test and chi-squared test considering a P &lt; 0.05 as statistical significance level. Results: There was no statistical difference between two groups regarding demographic variables. According to the obtained data, significantly higher MIF levels were observed in the affected subjects than the healthy individuals, particularly in severe COVID-19 subjects (severe: 65.31 ± 6.2 ng/mL, mild: 40.45 ± 6.6 ng/mL, healthy: 20.63 ± 6.1 ng/mL P &lt; 0.0001). The receiver operating characteristic (ROC curve) drawn for the present study illustrates that MIF amounts differentiate COVID-19 severe and mild cases with high accuracy (90.8%) (sensitivity:86.6%, specificity:96.6%). Conclusions: There might be an association between MIF concentration with respiratory failure and disease exacerbation due to COVID-19 infection. Therefore, MIF can act as a marker of clinical severity for COVID 19 infection. However, due to variations in MIF amounts a definite cut-off value might be specific to the study and should be considered with caution. MIF is supposed to be one of the most important cytokines in COVID-19 pathogenesis and might be a target for therapeutic approaches with MIF inhibitors in possible upcoming disease peaks.

Analysis of Macrophage Migration Inhibitory Factor Genotype in Hemophilia a Patients.

Hemophilia A, an X-linked bleeding disorder, is caused by a complete or partial deficiency in factor VIII. Multiple factors engage in the development and progression of bleeding episodes in hemophilia patients, especially arthropathy. Detection of macrophage migration inhibitory factor (MIF)-173 G/C polymorphism in people with hemophilia A (PWH) and the possible associations between the type of MIF gene polymorphism and selected disease-related variables. This case-control study included 95 male patients with hemophilia A and 95 non-hemophiliac subjects, all aged from 2 months to 63 years. An allele-specific polymerase chain reaction (AS-PCR) with a multiplex technique was used to detect MIF polymorphisms. A significantly higher frequency of GG polymorphism was reported in the control group (81, 85.3%) compared to PWH (64, 67.4%), while a significantly higher frequency of GC polymorphism was found in PWH (21, 22.1%) than that in healthy subjects (10, 10.5%), P < 0.05. The G allele polymorphism was detected in 90.0% of the control group compared to 78.4% of PWH (149 subjects), while the C allele frequency was higher in PWH (41, 21.6%) compared to that in healthy individuals (18, 10.0%), P < 0.05. The frequencies of varied MIF-173 polymorphisms did not show significant differences among patients with different clinical presentations or in relation to presence of inhibitors, P > 0.05. MIF-173 GC polymorphism is seen in PWH more than that in healthy individuals. Further studies are required to detect additional SNPs through sequencing of the MIF gene and to detect MIF serum levels during bleeding episodes.

The Relevance of Serum Macrophage Migration Inhibitory Factor Level and Executive Function in Patients with White Matter Hyperintensity in Cerebral Small Vessel Disease

(1) Objective: To investigate the relationship between serum macrophage migration inhibitory factor (MIF) level and white matter hyperintensity (WMH) and executive function (EF) in cerebral small vascular disease (CSVD), and assess the impact and predictive value of MIF level and Fazekas scores in CSVD-related cognitive impairment (CI) (CSVD-CI); (2) Methods: A total of 117 patients with WMH admitted to the First Affiliated Hospital of Xinxiang Medical College from January 2022 to August 2022 were enrolled. According to the Montreal cognitive assessment (MoCA) scale, subjects were divided into a normal cognitive group and an impaired group. All subjects required serum MIF level, 3.0 T MRI, and neuropsychological evaluation to investigate the risk factors for CDVD-CI, analyze the correlation between MIF level, WMH, and EF, and to analyze the diagnostic value of MIF and WMH degree in predicting CSVD-CI; (3) Results: 1. Fazekas score and MIF level were the risk factors of CSVD-CI. 2. The Fazekas score was negatively correlated with MoCA score, positively correlated with Stroop C-Time, Stroop C-Mistake, Stroop interference effects (SIE)-Time, SIE-Mistake, and color trails test (CTT) interference effects (CIE) (B-A). 3. The MIF level was positively correlated with Fazekas score, Stroop C-Time, SIE-Time, CTT B-Time, and CIE (B-A), and negatively correlated with MoCA score. 4. Fazekas score and MIF level were significant factors for diagnosing CSVD-CI; (4) Conclusion: The Fazekas score and MIF level may be the risk factors of CSVD-CI, and they are closely correlated to CI, especially the EF, and they have diagnostic value for CSVD-CI.

Elevated concentrations of macrophage migration inhibitory factor in serum and cerebral microdialysate are associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Inflammation is increasingly recognized to be involved in the pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) and may increase the susceptibility to delayed cerebral ischemia (DCI). Macrophage migration inhibitory factor (MIF) has been shown to be elevated in serum and cerebrospinal fluid (CSF) after aSAH. Here, we determined MIF levels in serum, CSF and cerebral microdialysate (MD) at different time-points after aSAH and evaluated their clinical implications. MIF levels were measured in serum, CSF and MD obtained from 30 aSAH patients during early (EPd1-4), critical (CPd5-15) and late (LPd16-21) phase after hemorrhage. For subgroup analyses, patients were stratified based on demographic and clinical data. MIF levels in serum increased during CPd5-15 and decreased again during LPd16-21, while CSF levels showed little changes over time. MD levels peaked during EPd1-4, decreased during CPd5-15 and increased again during LPd16-21. Subgroup analyses revealed significantly higher serum levels in patients with aneurysms located in the anterior vs. posterior circulation during CPd5-15 (17.3 [15.1-21.1] vs. 10.0 [8.4-11.5] ng/ml, p = 0.009) and in patients with DCI vs. no DCI during CPd5-15 (17.9 [15.1-22.7] vs. 11.9 [8.9-15.9] ng/ml, p = 0.026) and LPd16-21 (17.4 [11.7-27.9] vs. 11.3 [9.2-12.2] ng/ml, p = 0.021). In addition, MIF levels in MD during CPd5-15 were significantly higher in patients with DCI vs. no DCI (3.6 [1.8-10.7] vs. 0.2 [0.1-0.7] ng/ml, p = 0.026), while CSF levels during the whole observation period were similar in all subgroups. Our findings in a small cohort of aSAH patients provide preliminary data on systemic, global cerebral and local cerebral MIF levels after aSAH and their clinical implications. ClinicalTrials.gov, identifier: NCT02142166.

Distinct patterns of serum and urine macrophage migration inhibitory factor kinetics predict death in sepsis: a prospective, observational clinical study

Macrophage migration inhibitory factor (MIF) has been considered as a biomarker in sepsis, however the predictive value of the pattern of its kinetics in the serum and in the urine has remained unclarified. It is also unclear whether the kinetics of MIF are different between males and females. We conducted a single-center prospective, observational study with repeated measurements of MIF in serum and urine on days 0, 2, and 4 from admission to the intensive care unit (ICU) in 50 adult septic patients. We found that in patients who died within 90 days, there was an increase in serum MIF level from day 0 to 4, whereas in the survivors there was rather a decrease (p = 0.018). The kinetics were sex-dependent as the same difference in the pattern was present in males (p = 0.014), but not in females (p = 0.418). We also found that urine MIF was markedly lower in patients who died than in survivors of sepsis (p < 0.050). Urine MIF levels did not show temporal changes: there was no meaningful difference between day 0 and 4. These results suggest that kinetics of serum MIF during the initial days from ICU admission can predict death, especially in male patients. Additionally, lower urine MIF levels can also indicate death without showing meaningful temporal kinetics.

Macrophage Migration Inhibitory Factor in Major Depressive Disorder: A Multilevel Pilot Study.

Macrophage migration inhibitory factor (MIF) is a controversially discussed inflammatory marker in major depressive disorder (MDD). While some studies show an association of high MIF protein levels with depression, animal models have yielded conflicting results. Thus, it remains elusive as to whether MIF plays an anti- or pro-depressive role. Therefore, we aimed to examine the potential of MIF at the genetic, expression and protein levels as a risk factor and biomarker to diagnose, monitor, or predict the course of MDD. Patients with a current major depressive episode (n = 66 with, and n = 63 without, prior medication) and remitted patients (n = 39) were compared with healthy controls (n = 61). Currently depressed patients provided a second blood sample after three weeks of therapy. Depression severity was assessed by self-evaluation and clinician rating scales. We genotyped for three MIF polymorphisms and analyzed peripheral MIF expression and serum levels. The absence of minor allele homozygous individuals in the large group of 96 female patients compared with 10-16% in female controls suggests a protective effect for MDD, which was not observed in the male group. There were no significant group differences of protein and expression levels, however, both showed predictive potential for the course of depression severity in some subgroups. While MIF protein levels, but not MIF expression, decreased during treatment, they were not associated with changes in depression severity. This project is the first to investigate three biological levels of MIF in depression. The data hint toward a genetic effect in women, but do not provide robust evidence for the utility of MIF as a biomarker for the diagnosis or monitoring of MDD. The observed predictive potential requires further analysis, emphasizing future attention to confounding factors such as sex and premedication.

MIF is a common genetic determinant of COVID-19 symptomatic infection and severity.

Genetic predisposition to coronavirus disease 2019 (COVID-19) may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. This retrospective case-control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the USA, Hungary and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8,rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls [11% vs. 19%, odds ratio (OR) 0.54 [0.41-0.72], P < 0.0001]. Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR 2.87 [1.42-5.78], P = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, P < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, P = 0.01) and maximum CRP (r = 0.16, P = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of the high-expression CATT7MIF allele, which occurs in 19% of the population, in different stages of COVID-19 infection.

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.

Astaxanthin ameliorates serum level and spinal expression of macrophage migration inhibitory factor following spinal cord injury.

Astaxanthin (AST) is a lipid-soluble carotenoid with antioxidant and anti-inflammatory properties. Previous reports demonstrated the promising effects of AST on spinal cord injury (SCI)-induced inflammation and sensory-motor dysfunction. Macrophage migration inhibitory factor (MIF), as a cytokine, plays a critical role in the inflammatory phase of SCI. The aim of this study was to evaluate the effects of AST on post-SCI levels of MIF in serum and spinal cord. The possible correlation between MIF and mechanical pain threshold was also assessed. Adult male rats were subjected to a severe compression spinal injury and 30 min later were treated with AST (Intrathecal, 2 nmol) or vehicle. Neuropathic pain was assessed by von Frey filaments before the surgery, and then on days 7, 14, 21, and 28 post-SCI. Western blot and ELISA were used to measure the serum level and spinal expression of MIF following SCI in the same time points. AST treatment significantly attenuated the SCI-induced dysregulations in the serum levels and tissue expression of MIF. A negative correlation was observed between mechanical pain threshold and serum MIF level (r = -0.5463, P &lt; 0.001), as well as mechanical pain threshold and spinal level of MIF (r = -0.9562; P &lt; 0.001). AST ameliorates SCI-induced sensory dysfunction, probably through inhibiting MIF-regulated inflammatory pathways.

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.