Macrophage Migration Inhibitory Factor Plasma Levels Research Articles

Macrophage Migration Inhibitory Factor Promotes Thromboinflammation and Predicts Fast Progression of Aortic Stenosis.

Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.

Macrophage Migration Inhibitory Factor (MIF) Promotes Increased Proportions of the Highly Permissive Th17-like Cell Profile during HIV Infection.

In this study, we evaluate the role of the MIF/CD74 axis in the functionality of CD4+ T lymphocytes (CD4TL) during HIV infection. MDMs from healthy donors were infected with a R5-tropic or Transmitted/Founder (T/F) HIV strain. At day 11 post-MDM infection, allogeneic co-cultures with uninfected CD4TLs plus MIF stimulus were performed. Cytokine production was evaluated by ELISA. MIF plasma levels of people with HIV (PWH) were evaluated by ELISA. The phenotype and infection rate of CD4TLs from PWH were analyzed after MIF stimulus. Intracellular cytokines and transcription factors were evaluated by flow cytometry. Data were analyzed by parametric or non-parametric methods. The MIF stimulation of HIV-infected MDMs induced an increased expression of IL-6, IL-1β and IL-8. In CD4TL/MDM co-cultures, the MIF treatment increased IL-17A/RORγt-expressing CD4TLs. Higher concentrations of IL-17A in supernatants were also observed. These results were recapitulated using transmitted/founder (T/F) HIV-1 strains. The MIF treatment appeared to affect memory CD4TLs more than naïve CD4TLs. MIF blocking showed a negative impact on IL17A+CD4TL proportions. Higher MIF concentrations in PWH-derived plasma were correlated with higher IL-17A+CD4TL percentages. Finally, MIF stimulation in PWH-derived PBMCs led to an increase in Th17-like population. MIF may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs, which are known to be highly susceptible to HIV-1 infection and relevant to viral persistence. These observations establish a basis for considering MIF as a possible therapeutic target.

Macrophage migration inhibitory factor in Nodding syndrome.

Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)–a parasitic worm transmitted to human by blackflies. NS seems to be an ’Autoimmune Epilepsy’ in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a −794 CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS. Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy.

MIF plasma level as a possible tool to predict steroid responsiveness in children with idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome (INS) is the most frequent form of childhood nephrotic syndrome. Steroids represent the best therapeutic option; however, inter-individual differences in their efficacy and side effects have been reported. To date, there is no way to predict patients' resistance and/or dependence. Alterations in the cytokine profile of INS patients might contribute to proteinuria and glomerular damage and affect drug sensitivity. The cytokine plasma levels were measured in 21 INS children at diagnosis to investigate the association among cytokines pattern and clinical response. Patients were selected on the basis of their clinical response: 7 steroid sensitive (SS), 7 dependent (SD), and 7 resistant (SR). Significant results were then analyzed in 41 additional pediatric INS patients. Within the 48 cytokines analyzed, macrophage migration inhibitory factor (MIF) was a good predictor of steroid response. Indeed, SR patients showed significantly higher MIF plasma levels compared with all others (p = 0.022; OR = 4.3, 95%CI = 1.2-25.4): a cutoff concentration of MIF > 501pg/ml significantly discriminated SR patients (sensitivity = 85.7%, specificity = 71.4%). On the contrary, SD patients showed lower MIF plasma levels compared with others (p = 0.010; OR = 0.12, 95%CI = 9.2 × 10-3-6.7 × 10-1). Significant results were confirmed in the entire cohort. Our comprehensive cytokine analysis indicates that assessing MIF plasma levels at diagnosis could predict response to glucocorticoids in children with INS.

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

Macrophage Migration Inhibitory Factor is Associated with Biomarkers of Alzheimer's Disease Pathology and Predicts Cognitive Decline in Mild Cognitive Impairment and Mild Dementia.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimer's disease (AD) pathology. To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression. CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aβ1-42, tau, and ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits. CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aβ1-42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aβ1-42 and tau levels. Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia.

Renal replacement therapy neutralizes elevated MIF levels in septic shock.

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

Filtration of Macrophage Migration Inhibitory Factor (MIF) in Patients with End Stage Renal Disease Undergoing Hemodialysis.

BackgroundEnd stage renal disease (ESRD) patients are characterized by increased morbidity and mortality due to highest prevalence of cardiovascular disease. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that controls cellular signaling in human physiology, pathophysiology, and diseases. Increased MIF plasma levels promote vascular inflammation and development of atherosclerosis. We have shown that MIF is associated with vascular dysfunction in ESRD patients. Whether hemodialysis (HD) affects circulating MIF plasma levels is unknown. We here aimed to investigate whether HD influences the circulating MIF pool in ESRD patients.Methods and ResultsAn observational single-center study was conducted. MIF plasma levels in ESRD patients were assessed before, during, and after a HD session (n = 29). Healthy age-matched volunteers served as controls to compare correlations of MIF plasma levels with inflammatory plasma components (n = 20). MIF removed from the circulating blood pool could be detected in the dialysate and allowed for calculation of totally removed MIF (MIF content in dialysate 219±4 μg/HD-session). MIF plasma levels were markedly decreased 2 hour after initiation of HD (MIF plasma level pre-HD 84.8±6 ng/ml to intra-HD 61.2±5 ng/ml p<0.001) and were replenished already 20 min after termination of HD to basal levels (intra-HD 61.2±5 ng/ml to post-HD 79.8±5 ng/ml, p<0.001).ConclusionMIF is a dialyzable plasma component that is effectively filtrated during HD from the patient blood pool in large amounts. After removal of remarkable amounts of MIF during a single HD session, MIF plasma pool is early reconstituted after termination of HD from unknown sources.

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.

155. Correlation of elevated MIF and tyrosine plasma levels in pregnancy

A cross-sectional, correlational pilot study evaluating macrophage migration inhibitory factor (MIF) in plasma samples collected at early second trimester from 40 healthy pregnant women found a positive correlation between plasma MIF (ELISA) and plasma tyrosine (HPLC) ( r = 0.43, p < 0.008) levels. MIF functions as a proinflammatory cytokine, participates in glucocorticoid (e.g. cortisol) regulation via the MIF/glucocorticoid dyad, and is an increasingly important small molecule involved in modulation of neuroendocrine-immune crosstalk. Tyrosine motifs participate extensively in scaffolding phosphorylation and receptor/nonreceptor signaling; furthermore, nonreceptor tyrosine kinases have been shown to be activated by CD44, the signaling component of the MIF-CD74 complex. Potential key aspects of a correlation between MIF and tyrosine may be their mutual involvement in the persistence of B cells (a Th2 immune hallmark) with related survival signaling (e.g. MIF-CD74 induction), equilibrium in MIF glucocorticoid regulation, and a possible role in the Type 1 to Type 2 immune shift during pregnancy with resulting altered homeostasis and inflammation. Research suggests MIF and tyrosine levels may have a role in TLR-induced signaling directly bridging the innate to adaptive immune response (e.g. DAMP). Seemingly these factors also could demonstrate further significance when assessing pregnancy outcomes. In addition, expanded assessment of this correlation may illuminate specific mechanisms by which MIF and tyrosine in the periphery may cross the BBB and/or have a role in modulating neuroendocrine-immune interactions in the CNS.

Macrophage migration inhibitory factor is associated with vascular dysfunction in patients with end-stage renal disease

BackgroundPatients with end-stage renal disease (ESRD) show a high prevalence of cardiovascular disease with arterial stiffness, atherosclerosis and endothelial dysfunction, leading to increased morbidity and mortality. The cytokine macrophage migration inhibitory factor (MIF) exhibits proinflammatory and proatherogenic functions and has recently emerged as a major regulator of atherogenesis. Studies examining the relationship between circulating MIF levels and vascular dysfunction in this high-risk population do not exist. MethodsIn patients with ESRD (n=39) and healthy controls (n=16) we assessed endothelial function by flow-mediated dilation of the brachial artery and arterial stiffness (augmentation pressure, augmentation index and pulse pressure) using applanation tonometry. High-sensitive Troponin and subendocardial viability ratio were determined to assess myocardial injury. ResultsPatients with ESRD had impaired endothelial function and higher plasma MIF levels. MIF levels negatively correlated with endothelial function (r=−0.345, P=0.031) and positively with arterial stiffness indices in patients with ESRD (pulse pressure r=−0.374, P=0.019 and augmentation pressure r=−0.423, P=0.025). In multivariate regression models besides age, gender, weight, and heart rate, MIF was an independent predictor for arterial stiffness. Impact on myocardial end-organ damage was reflected by correlation with high-sensitive Troponin I (r=0.43, P=0.009). ConclusionOur findings show that high MIF plasma levels are associated with diminished endothelial function and arterial stiffness and are correlated with myocardial injury. Further studies are necessary to investigate whether modulation of MIF might have an impact on atherosclerotic disease in this high-risk population.

Decreased Plasma Levels of Clusterin in Patients With Psoriasis

Introduction and objectivesPsoriasis is a chronic inflammatory disease that has been linked to increased cardiovascular risk. The glycoprotein clusterin (apolipoprotein J) is a component of high-density lipoproteins and has a protective role in atherosclerosis. The aim of the present study was to evaluate the plasma levels of clusterin and the proinflammatory cytokine macrophage migration inhibitory factor (MIF) in patients with severe psoriasis, comparing groups of patients with different risks of cardiovascular disease. Material and methodsTwenty-one patients with severe psoriasis (psoriasis area severity index and body surface area>10) and 11 healthy controls with no dermatologic disease were studied. Cardiovascular risk factors were assessed according to the Adult Treatment Panel (ATP) III criteria. Subclinical carotid atheromatosis was assessed by Doppler ultrasonography of the carotid arteries. Plasma clusterin and MIF levels were measured by enzyme-linked immunosorbent assay. ResultsATP-III criteria for metabolic syndrome were met by 47% of the patients, and 33% had carotid atheromatous plaque. Mean (SD) clusterin plasma levels were significantly lower in patients with psoriasis compared with controls (81.39 [27.30] μg/mL for the 21 patients vs 117 [21.6] μg/mL for the 11 controls; P=.0017). MIF plasma levels (ng/ml) were significantly higher in patients with atheromatous plaque compared with controls (53.22 [29.02] for the 6 patients with plaque vs 34.21 [9.65] for the 11 controls; P=.0394). ConclusionsThe decreased plasma levels of clusterin in psoriatic patients suggested an association with the disease and might be an indicator of systemic inflammatory activity. Increased levels of MIF appear to be associated with cardiovascular risk factors and carotid atheromatous plaque.

Disminución de los niveles plasmáticos de clusterina en pacientes con psoriasis

Introduction and objectivesPsoriasis is a chronic inflammatory disease that has been linked to increased cardiovascular risk. The glycoprotein clusterin (apolipoprotein J) is a component of high-density lipoproteins and has a protective role in atherosclerosis. The aim of the present study was to evaluate the plasma levels of clusterin and the proinflammatory cytokine macrophage migration inhibitory factor (MIF) in patients with severe psoriasis, comparing groups of patients with different risks of cardiovascular disease. Material and methodsTwenty-one patients with severe psoriasis (psoriasis area severity index and body surface area>10) and 11 healthy controls with no dermatologic disease were studied. Cardiovascular risk factors were assessed according to the Adult Treatment Panel (ATP) III criteria. Subclinical carotid atheromatosis was assessed by Doppler ultrasonography of the carotid arteries. Plasma clusterin and MIF levels were measured by enzyme-linked immunosorbent assay. ResultsATP-III criteria for metabolic syndrome were met by 47% of the patients, and 33% had carotid atheromatous plaque. Mean (SD) clusterin plasma levels were significantly lower in patients with psoriasis compared with controls (81.39 [27.30] μg/mL for the 21 patients vs 117 [21.6] μg/mL for the 11 controls; P=.0017). MIF plasma levels (ng/ml) were significantly higher in patients with atheromatous plaque compared with controls (53.22 [29.02] for the 6 patients with plaque vs 34.21 [9.65] for the 11 controls; P=.0394). ConclusionsThe decreased plasma levels of clusterin in psoriatic patients suggested an association with the disease and might be an indicator of systemic inflammatory activity. Increased levels of MIF appear to be associated with cardiovascular risk factors and carotid atheromatous plaque.

Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus

To study the effect of the innate cytokine macrophage migration inhibitory factor (MIF) on the susceptibility and severity of systemic lupus erythematosus (SLE) in a multinational population of 1,369 Caucasian and African American patients. Two functional polymorphisms in the MIF gene, a -794 CATT(5-8) microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were assessed for association with SLE in 3,195 patients and healthy controls. We also measured MIF plasma levels in relation to genotypes and clinical phenotypes, and assessed Toll-like receptor 7 (TLR-7)-stimulated MIF production in vitro. Both Caucasians and African Americans with the high-expression MIF haplotype -794 CATT(7)/-173*C had a lower incidence of SLE (in Caucasians, odds ratio [OR] 0.63, 95% confidence interval [95% CI] 0.53-0.89, P = 0.001; in African Americans, OR 0.46, 95% CI 0.23-0.95, P = 0.012). In contrast, among patients with established SLE, reduced frequencies of low-expression MIF genotypes (-794 CATT(5)) were observed in those with nephritis, those with serositis, and those with central nervous system (CNS) involvement when compared to patients without end-organ involvement (P = 0.023, P = 0.005, and P = 0.04, respectively). Plasma MIF levels and TLR-7-stimulated MIF production in vitro reflected the underlying MIF genotype of the studied groups. These findings suggest that MIF, which has both proinflammatory properties and macrophage and B cell survival functions, exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE and may contribute to an enhanced clearance of infectious pathogens. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage.

49: Downregulation of macrophage Migration Inhibitory Factor (MIF) by insulin during the steady state plasma glucose test, new insights in MIF regulation

MIF is a cytokine associated with insulin resistance (IR). Increased MIF plasma levels were reported in morbidly obese patients. Moreover, MIF mRNA expression in mononuclear cells (MC) were increased in morbid obesity.

A single nucleotide polymorphism of macrophage migration inhibitory factor is related to inflammatory response in coronary bypass surgery using cardiopulmonary bypass

Cardiac surgery causes induction and release of inflammatory mediators that may be regulated by genetic background. Macrophage migration inhibitory factor (MIF) is a proinflammatory mediator that is known to be up-regulated in patients undergoing cardiac operations. Here we analyzed genotype distribution and allele frequency of the MIF-173*G/C single nucleotide polymorphism (SNP) and MIF plasma levels in patients undergoing surgical revascularization with (on-pump, n=45) and without (off-pump, n=34) cardiopulmonary bypass (CPB). Genotyping was performed using a real-time PCR-based system with a hybridization probe system specific for the MIF-173*G/C SNP. In on-pump patients, blood samples were drawn before start of CPB, after termination of CPB and 12h postoperatively. In off-pump patients, blood samples were collected before stabilizer placement, after removal of the stabilizer and 12h postoperatively. MIF levels were measured using ELISA technique. Genotype distribution and allele frequencies were comparable between on-pump and off-pump patients. When comparing patients according to MIF genotype, a significant increase of MIF plasma levels after completed coronary bypass grafting using CPB was found in patients heterozygous for the MIF-173*G/C SNP (p<0.05). Moreover, on-pump patients showed significantly decreased MIF plasma levels after 12h postoperatively (p<0.05). In off-pump patients, MIF plasma levels were not significantly different over the time-course and were independent of the genotype. Patients carrying the C-allele showed significantly increased levels of the proinflammatory cytokine MIF compared to G/G homozygous when revascularization was carried out using CPB. The G/C genotype may be associated with a severe inflammatory reaction and therefore preoperative screening could be beneficial for patients undergoing cardiac surgery using CPB.

Macrophage migration inhibitory factor (MIF) seems crucially involved in Guillain–Barré syndrome and experimental allergic neuritis

Macrophage migration inhibitory factor (MIF) is a proinflammatory type 1 cytokine that plays a pathogenic role in several inflammatory and autoimmune diseases. The role of this cytokine in peripheral nerve inflammatory disease has not been evaluated. Therefore, to evaluate the role of macrophage migration inhibitory factor (MIF) in Guillain–Barré syndrome (GBS) and experimental allergic neuritis (EAN), we determined MIF circulating levels in a series of patients with GBS and healthy subjects with ELISA and evaluated the effect of two specific inhibitors of MIF, a neutralizing monoclonal antibody or a chemical inhibitor ISO1 on the course of murine EAN. The data show increased MIF plasma levels in GBS patients as compared to healthy controls ( p < 0.0001) and a progressive increase of MIF circulating concentration with patient's disability ( p < 0.0001). Both anti-MIF mAb and ISO1 favorably influenced the course of EAN. Treated mice had a lower cumulative severity score ( p = 0.001) and reduced disease duration than the control mice ( p < 0.03). MIF may promote immune reaction in GBS. Therapeutic effects of both anti-MIF mAb and ISO1 in EAN suggest that MIF could be a promising therapeutic target in inflammatory demyelinating peripheral nerve disorders.

Macrophage migration inhibitory factor delays apoptosis in neutrophils by inhibiting the mitochondria-dependent death pathway.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine known to activate macrophages and T cells. In this study, we demonstrate that recombinant MIF delays apoptosis of neutrophils in vitro. MIF action is dose and time dependent as well as specific since it was abolished with a neutralizing anti-MIF antibody. MIF, like G-CSF, delayed cleavage of the proapoptotic members of the Bcl-2 family Bid and Bax in neutrophils, suggesting that MIF inhibits apoptosis pathways proximal to mitochondria activation. Indeed, MIF also prevented release of cytochrome c and Smac from the mitochondria and subsequent activation of the critical effector caspase-3 in these cells. Moreover, we observed increased MIF plasma levels in patients with cystic fibrosis, a heterogeneous recessive genetic disorder associated with bacterial infections and delayed neutrophil apoptosis. In conclusion, MIF is a survival cytokine for human neutrophils, a finding with potential pathologic relevance in infectious diseases.