Plasma Macrophage Migration Inhibitory Factor Levels Research Articles

A possible link between luteinizing hormone and macrophage migration inhibitory factor levels in polycystic ovary syndrome

ABSTRACTPurpose: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that plays a role in metabolic and inflammatory processes. Increasing evidence suggests that there is a link between MIF and ovulation. We aimed to evaluate plasma MIF levels in women with polycystic ovary syndrome (PCOS) and to determine whether MIF levels differ between the follicular phase and mid-cycle of the menstrual cycle in eumenorrheic women. Methods: Ninety women with PCOS and 80 age- and BMI-matched healthy eumenorrheic women were consecutively recruited into this prospective observational study. For all subjects, plasma MIF levels in the early follicular phase were measured by ELISA; for the 40 healthy controls, MIF levels were also measured during mid-cycle of the same menstrual cycle. Results: Plasma MIF levels were significantly higher in women with PCOS than in eumenorrheic women (14.16 ± 1.59 vs. 10.39 ± 0.70 ng/ml; p < 0.001). MIF levels were significantly higher at mid-cycle than in the follicular phase in eumenorrheic women (11.15 ± 0.61 vs. 10.56 ± 0.82 ng/ml; p < 0.001). MIF was positively correlated with BMI, high sensitivity C-reactive protein (hs-CRP), and homeostasis model assessment of insulin resistance (HOMA-IR) in both groups. MIF was positively correlated with luteinizing hormone (LH) and free-testosterone only in the PCOS group. Binary logistic regression analyses revealed that the odds ratio (OR) for PCOS independently increases linearly with elevated MIF (OR = 1.385, 95% CI = 1.087–1.764, p = 0.017). Conclusion: MIF may play a crucial role in the reproductive system in women, including the development of PCOS and normal ovulation.

Macrophage Migration Inhibitory Factor in Clinical Kidney Disease.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine implicated in acute and chronic inflammatory conditions, including sepsis, autoimmune disease, atherogenesis, plaque instability, and pulmonary arterial hypertension. MIF in plasma and urine is significantly elevated in patients with acute kidney injury (AKI) and elevated MIF in serum is associated with markers of oxidative stress, endothelial dysfunction, arterial stiffness, and markers of myocardial damage in chronic kidney disease (CKD). Furthermore, MIF seems to be involved in vascular processes and cardiovascular disease associated with CKD, glomerulonephritis, autosomal dominant polycystic kidney disease, and possibly also in progression to renal failure. Moreover, in active anti-neutrophil cytoplasmatic antibody-associated vasculitis, plasma MIF levels have been shown to be significantly elevated as compared with samples from patients in remission. A significant difference in the genotype frequency of high production MIF -173 G/C genotype has been found in end-stage renal disease, compared to controls. Inhibition of MIF in a diabetic nephropathy model ameliorated blood glucose and albuminuria and in a model of adult polycystic kidney disease cyst growth was delayed. Preclinical studies support a potential therapeutic role for MIF in AKI and in a number of CKDs, whereas these data in human disease are still observational. Future interventional studies are needed to delineate the role of MIF as a treatment target in clinical kidney disease.

The Association of Higher Plasma Macrophage Migration Inhibitory Factor Levels with Lower Bone Mineral Density and Higher Bone Turnover Rate in Postmenopausal Women.

BackgroundDespite evidence from animal and clinical studies showing the detrimental effects of macrophage migration inhibitory factor (MIF) on bone metabolism, there are no clinical studies relating circulating MIF levels to osteoporosis-related phenotypes. This cross-sectional study investigated the association of plasma MIF with bone mineral density (BMD), bone turnover markers (BTMs), and prevalence of osteoporosis in postmenopausal Korean women.MethodsA total of 246 women not taking any medications or diagnosed with any diseases that could affect bone metabolism were enrolled. BMD values at the lumbar spine, femoral neck, and total femur, and blood levels of MIF and BTMs were measured in all subjects. Osteoporosis was defined by World Health Organization criteria.ResultsBefore and after adjustment for confounding variables, higher MIF levels were significantly associated with lower BMD values at all measured sites and higher levels of all BTMs. All BMD values and BTMs significantly changed in a dose-dependent fashion across increasing MIF quartile. When participants were divided into two groups according to osteoporosis status, postmenopausal women with osteoporosis demonstrated 24.2% higher plasma MIF levels than those without osteoporosis (P=0.041). The odds ratio per each standard deviation increment of MIF levels for prevalent osteoporosis was 1.32 (95% confidence interval, 1.01 to 1.73).ConclusionThis study provides the first epidemiological evidence that higher plasma MIF may be associated with higher risk of osteoporosis resulting from lower bone mass and higher bone turnover rate, and thus it could be a potential biomarker of poor bone health outcomes in postmenopausal women.

Attenuation of atherosclerotic lesions in diabetic apolipoprotein E-deficient mice using gene silencing of macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) involves the pathogenesis of atherosclerosis (AS) and increased plasma MIF levels in diabetes mellitus (DM) patients are associated with AS. Here, we have been suggested that MIF could be a critical contributor for the pathological process of diabetes-associated AS by using adenovirus-mediated RNA interference. First, streptozotocin (STZ)-induced diabetic animal model was constructed in 114 apolipoprotein E-deficient mice (apoE−/− mice) fed on a regular chow diet. Then, the animals were randomly divided into three groups: Adenovirus-mediated MIF interference (Ad-MIFi), Ad-enhanced green fluorescent protein (EGFP) and normal saline (NS) group (n ≈ 33/group). Non-diabetic apoE−/− mice (n = 35) were served as controls. Ad-MIFi, Ad-EGFP and NS were, respectively, injected into the tail vein of mice from Ad-MIFi, Ad-EGFP and NS group, which were injected repeatedly 4 weeks later. Physical, biochemical, morphological and molecular parameters were measured. The results showed that diabetic apoE−/− mice had significantly aggravated atherosclerotic lesions. MIF gene interference attenuated atherosclerotic lesions and stabilized atheromatous plaque, accompanied by the decreased macrophages and lipids deposition and inflammatory cytokines production, improved glucose intolerance and plasma cholesterol level, the decreased ratio of matrix matalloproteinase-2/tissue inhibitor of metalloproteinase-1 and plaque instability index. An increased expression of MIF and its ligand CD74 was also detected in the diabetic patients with coronary artery disease. The results suggest that MIF gene interference is able to inhibit atherosclerotic lesions and increase plaque stability in diabetic apoE−/−mice. MIF inhibition could be a novel and promising approach to the treatment of DM-associated AS.

Abstract T MP14: The Critical Role of Macrophage Migration Inhibitory Factor on Post-Stroke Recovery

Objective: One-third of stroke survivors are affected by post-stroke depression. Evidence from epidemiological and clinical studies demonstrates that depression either before or after stroke is associated with poor recovery and high mortality. Recently it was found that loss of macrophage migration inhibitory factor (MIF) is associated with depressive behavior and impaired neurogenesis. Therefore, here we tested the hypothesis that MIF plays a role in stroke recovery and that chronic MIF inhibition contributes to post-depressive phenotypes and poor stroke outcomes. Methods: C57BL/6 male mice (20-25g; Charles River), were subjected to a 60min right middle cerebral artery occlusion (MCAO) and randomly assigned to vehicle or MIF antagonist, ISO-1 (7mg/kg/day intraperitoneal) treatment. Infarcts quantified with TTC. Recovery was investigated using neurological deficit scores (NDS), corner test, the forced swim test (FST) and the tail suspension test (TST). MIF levels were assessed by ELISA and western-blot (n=4/grp). Further, the effects of MIF loss were tested using knockout (KO) mice. Data are expressed as mean±sem. P value &lt; .05 was set for statistical significance. Results: Post-stroke chronic ISO-1 treatment significantly increased immobility in TST at 14d (126±8 vs 83±6s; p&lt;.05), delayed stroke recovery in the corner test (p&lt;.05) and NDS (p&lt;.05) compared to vehicle group. These detrimental effects were observed in parallel to reduced plasma MIF levels (p&lt;.05). Stroke alone did not affect mobility in FST compared to sham (p&gt;.05). Infarct size was similar in ISO-1 and vehicle groups (48±3.2% versus 46±2.8%; p&gt;.05). When subjected MIF KO mice to stroke, similar pattern of delayed post-stroke recovery is observed suggesting that MIF plays a critical role in pre- or post-stroke depression and recovery. Conclusions: MIF KO mice had a depressive phenotype at baseline, and poor recovery after stroke compared to WT. Post-stroke MIF inhibition led to the development of a post-stroke depressive phenotype and also led to poorer recovery. These effects are independent of stroke volume. These findings suggest that targeting MIF might be a novel therapeutic strategy to treat post-stroke depression and to enhance recovery in stroke survivors.

Macrophage migration inhibitory factor in obese and non obese women with polycystic ovary syndrome

Objective: To measure macrophage migration inhibitory factor (MIF) concentrations in obese and non-obese women diagnosed with polycystic ovary syndrome (PCOS). Methods: Women diagnosed with PCOS and age-matched healthy controls with regular menses and normal ovaries on ultrasound examination were selected and divided into 4 groups (group A, PCOS and obese; group B, PCOS and non-obese; group C, obese controls; and group D, non-obese controls) based on body mass index (obese >30 kg/m 2 and non-obese <25 kg/m 2 ). Luteinizing hormone, follicle-stimulating hormone, androstenedione, testosterone, sex hormone-binding globulin, serum glucose, insulin and MIF levels were measured. Results: Obese and non-obese women with PCOS had higher luteinizing hormone, folliclestimulating hormone, androstenedione, testosterone, and insulin levels as compared to the obese and non-obese control groups, respectively (P < .0001). Women with PCOS had significantly higher MIF levels (group A, 48.6 ± 9.9 mg/ml; group B, 35.2 ± 6.0 ng/ml) as compared to controls (group C, 13.5 ± 6.0 ng/ml; group D, 12.0 ± 4.3 ng/dl; P < .0001). A weak, positive and significant correlation was seen between fasting blood glucose and insulin levels in women with PCOS (P < .05). Conclusion: Significant differences exist in plasma MIF levels between obese and non-obese women with and without PCOS.

Elevated Circulating Levels of the Pro-Inflammatory Cytokine Macrophage Migration Inhibitory Factor in Individuals With Acute Spinal Cord Injury

ObjectiveTo test the hypothesis that macrophage migration inhibitory factor (MIF) is elevated in the circulation of individuals with acute spinal cord injury (SCI) compared with uninjured individuals. DesignProspective, observational pilot study. SettingAcademic medical center. ParticipantsAdults with acute traumatic SCI (n=18) and uninjured participants (n=18), comparable in age and sex distribution. InterventionsNot applicable. Main Outcome MeasuresThe primary outcome measure was the plasma MIF levels. Potential correlations were examined between MIF and clinical/demographic variables. The secondary outcome was to determine if other immune mediators were elevated in participants with acute SCI and if their levels correlated with the MIF. ResultsMIF was significantly elevated in subjects with acute SCI compared with control subjects at 0 to 3 (P<.0029), 4 to 7 (P<.0001), and 8 to 11 (P<.0015) days postinjury (DPI). At 0 to 3 DPI, levels of cytokines interleukin-6 (P<.00017), interleukin-9 (P<.0047), interleukin-16 (P<.007), interleukin-18 (P<.014), chemokines growth-related oncogene α/chemokine (C-X-C motif) ligand 1 (P<.0127) and macrophage inflammatory protein 1-β/chemokine (C-C motif) ligand 4 (P<.0015), and growth factors hepatocyte growth factor (HGF) (P<.0001) and stem cell growth factor-β (P<.0103) were also significantly elevated in subjects with acute SCI. With the exception of interleukin-9, all of these factors remained significantly elevated at 4 to 7 DPI; a subset (interleukin-16, HGF, stem cell growth factor-β) remained elevated throughout the study. Within individuals, MIF levels correlated with HGF (P<.018) and interleukin-16 (P<.01). ConclusionsThese data demonstrate that MIF is significantly elevated in subjects with acute SCI, supporting further investigation of MIF and other inflammatory mediators in acute SCI, where they may contribute to primary and secondary functional outcomes.

Factor inhibidor de la migración de macrófagos en mujeres obesas y no obesas con síndrome de ovarios poliquísticos

ObjectiveTo measure macrophage migration inhibitory factor (MIF) concentrations in obese and non-obese women diagnosed with polycystic ovary syndrome (PCOS). MethodWomen diagnosed with PCOS and age-matched healthy controls with regular mensese and normal ovaries on ultrasound examination were selected and divided into 4 groups (group A, PCOS and obese; group B, PCOS and non-obese; group C, obese controls; and group D, non-obese controls) based on body mass index (obese>30kg/m2 y non-obese<25kg/m2). Luteinizing hormone, follicle-stimulating hormone, androstenedione, testosterone, sex hormone-binding globulin, serum glucose, insulin and MIF levels were measured. ResultsObese and non-obese women with PCOS had higher luteinizing hormone, follicle-stimulating hormone, androstenedione, testosterone, and insulin levels as compared to the obese and non-obese control groups, respectively (P<.0001). Women with PCOS had significantly higher MIF levels (group A, 48.6±9.9mg/ml; group B, 35.2±6.0ng/ml) as compared to controls (group C, 13.5±6.0ng/ml; group D, 12.0±4.3ng/dl; P<.0001). A weak, positive and significant correlation was seen between fasting blood glucose and insulin levels in women with PCOS (P<.05). ConclusionSignificant differences exist in plasma MIF levels between obese and non-obese women with and without PCOS.

Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, secreted from a variety of immune cells, that regulates innate and adaptive immune responses. Elevation of MIF levels in plasma correlates with the severity of inflammatory diseases in humans. Inhibition of MIF or its tautomerase activity ameliorates disease severity by reducing inflammatory responses. In this study, the human single-chain variable fragment (HuScFv) antibody specific to MIF was selected from the human antibody phage display library by using purified recombinant full-length human MIF (rMIF) as the target antigen. Monoclonal HuScFv was produced from phage-transformed bacteria and tested for their binding activities to rMIF by indirect enzyme-linked immunosorbent assay as well as to native MIF by western blot analysis and immunofluorescence assay. The HuScFv with highest binding signal to rMIF also inhibited the tautomerase activities of both rMIF and native MIF in human monoblastic leukemia (U937) cells in a dose-dependent manner. Mimotope searching and molecular docking concordantly demonstrated that the HuScFv interacted with Lys32 and Ile64 in the MIF tautomerase active site. To the best of our knowledge, this is the first study to focus on MIF-specific fully-human antibody fragment with a tautomerase-inhibitory effect that has potential to be developed as anti-inflammatory biomolecules for human use.

Modulation of circulating macrophage migration inhibitory factor in the elderly.

Aging increases the risk for cardiovascular morbidity and mortality. Chronic low-grade inflammation deteriorates vascular function, increases age-related vascular stiffness, and affects hemodynamics. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) is a major mediator of atherosclerosis. Plasma MIF levels are associated with arterial stiffness, a hallmark of vascular aging. Preclinical studies show that blockade of MIF leads to atherosclerotic plaque regression. Nutritional approaches provide opportunities to counteract age-related inflammation. Following a chronic dietary supplementation with the micronutrient nitrate has been demonstrated to improve vascular stiffness. Whether dietary nitrate affects circulating MIF levels is not known. In a randomized placebo-controlled, double-blinded study, elderly subjects received a dietary nitrate supplementation for 4 weeks. Dietary nitrate led to a decrease in plasma MIF levels in the elderly and to an improvement in vascular functions. This was associated with a reduction in central systolic blood pressure. Our data show that supplementation with dietary nitrate is associated with a reduction of circulating MIF levels along with an improvement in vascular function. This supports the concept of dietary approaches to modulate age-related changes of vascular functions.

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.

Tissue-specific regulation of inflammation by macrophage migration inhibitory factor and glucocorticoids in fructose-fed Wistar rats

High fructose consumption is commonly associated with insulin resistance, disturbed glucose homeostasis and low-grade inflammation. Increased glucocorticoid production within adipose tissue has been implicated in the pathogenesis of fructose-induced metabolic syndrome. Immunosuppressive actions of glucocorticoids can be counter-regulated by macrophage migration inhibitory factor (MIF), which is recognised as a key molecule in metabolic inflammation. In the present study, we hypothesised that coordinated action of glucocorticoids and MIF can mediate the effects of a high-fructose diet on adipose tissue and liver inflammation. We examined the effects of long-term consumption of a 10% fructose solution on corticosterone (CORT) and MIF levels in rat blood plasma, liver and adipose tissue, as well as MIF and TNF-a mRNA expression and NF-kB activation in the same tissues. The high-fructose diet led to an increase in both CORT and MIF in the adipose tissue, and a highly significant positive correlation between their levels was observed. The attenuated NF-kB activation and unaltered TNF-a mRNA expression noticed in the adipose tissue could be interpreted as an outcome of the opposing actions of CORT and MIF. In contrast to adipose tissue, inflammation in the liver was characterised by NF-kB activation, an increased TNF-a mRNA level and unchanged levels of MIF protein, MIF mRNA and CORT. Overall, these findings suggest that a high-fructose diet differently affects the levels of glucocorticoids and MIF in the adipose tissue and liver, implicating that fructose over-consumption has tissue-specific effects on regulation of metabolic inflammation.

A genetic role for macrophage migration inhibitory factor (MIF) in adult-onset Still's disease

IntroductionAdult-onset still's disease (AOSD) is a rare systemic inflammatory disorder in which abnormalities in inflammatory cytokines production appear to play a pathophysiological role. Our previous work has reported increased expression of macrophage migration inhibitory factor (MIF) and revealed its correlation with disease severity and activity in AOSD. A -173 G/C single nucleotide polymorphism (SNP) (rs755622) and a -794 CATT5-8 repeat (rs5844572) in the MIF promoter have been reported. In this study, we sought to explore the relationship between functional MIF promoter polymorphisms and MIF expression in AOSD.Methods100 patients and 200 controls were recruited in the study. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the -173 G/C SNP (rs755622) and PCR-based size discrimination assay was applied to detect the -794 CATT5-8 repeat (rs5844572) in the MIF promoter. Plasma MIF levels were measured by ELISA. MIF mRNA levels were quantified by real-time reverse transcription (RT)-PCR. Bisulfate genomic sequencing was employed to evaluate DNA methylation status within the MIF promoter.ResultsWe identified that the frequencies of MIF -794 CATT5 (P = 0.001) allele and the expression of MIF (P <0.001) were increased in patients compared to healthy controls. Plasma levels of MIF in patients with CC genotype were higher than those of patients with GC or GG genotypes (P = 0.05). In patients with established AOSD, a higher frequency of -794 CATT7 containing MIF genotypes was observed in those with liver dysfunction (P = 0.009). Haplotype analysis revealed a higher representation of the MIF haplotype defined by -173*C/-794 CATT5 (C5) in AOSD patients (P = 0.001).ConclusionFunctional promoter polymorphisms in the MIF gene influence plasma MIF levels in AOSD and may contribute to disease susceptibility or clinical presentation of AOSD.

Intervillous Macrophage Migration Inhibitory Factor Is Associated with Adverse Birth Outcomes in a Study Population in Central India

Macrophage migration inhibitory factor (MIF) is a pluripotent factor produced by a variety of cells. It plays an important biological role in the regulation of pregnancy and has been shown to influence malaria pathogenesis. In this study, the levels of MIF in the peripheral, cord and placental intervillous blood (IVB) plasma collected from women residing in a malaria endemic region of Central India was determined and its association with malaria in pregnancy and birth outcomes was investigated. MIF levels were significantly different in IVB, peripheral, and cord plasma, with IVB plasma having the highest MIF levels and peripheral plasma having the lowest. Placental malaria positive women had significantly higher IVB plasma MIF levels than placental malaria negative women, but this relationship was not seen in peripheral or cord plasma MIF levels. In addition, the odds of stillbirth and low birth weight deliveries for the uppermost placental MIF quartile (irrespective of placental malaria status) was significantly higher than that of the lowest placental MIF quartile, supporting the hypothesis that elevated concentrations of placental MIF may be associated with an increased risk of adverse birth outcome.

MIF, MIF Alleles, and Prospects for Therapeutic Intervention in Autoimmunity

Macrophage migration inhibitory factor (MIF) is an innate cytokine whose main actions include counter-regulating the immunosuppressive action of glucocorticoids and inhibiting activation-induced apoptosis. MIF is encoded in a functionally polymorphic locus and human genetic studies have shown significant relationships between high-expression MIF alleles, host inflammatory responses, and improved clinical outcome from infections. A recently completed candidate gene association study in the autoimmune disease systemic lupus erythematosus (SLE) indicates that individuals with a high-expression MIF allele have reduced incidence of SLE. Among patients with established disease however, those with end-organ complications have increased frequency of high-expression MIF alleles. Plasma MIF levels and Toll-like receptor (TLR) stimulated MIF production also reflect the underlying MIF genotype. These data suggest that MIF exerts a dual influence on the immunopathogenesis of SLE: high-expression MIF alleles are associated with a reduced susceptibility to SLE, perhaps by enhancing clearance of autoimmunogenic pathogens; once SLE develops however, low-expression MIF alleles protect from ensuing inflammatory end-organ damage. These data thus provide an example of the potential evolutionary advantage of maintaining an autoimmunity susceptibility gene in the population in that high-expression MIF alleles may allow for a maximal anti-infective response despite risk of autoimmunity. These results also support the clinical feasibility of pharmacologic MIF antagonism as such therapies may be most effectively applied in those individuals who, on the basis of their genotype, manifest a MIF dependent form of autoimmunity.

Role of MIF gene polymorphisms in systemic lupus erythematosus and prospects for therapeutic intervention

The cytokine macrophage migration inhibitory factor (MIF) counter-regulates the immunosuppressive action of glucocorticoids and inhibits activation-induced apoptosis. MIF is encoded in a polymorphic locus with a variant allele frequency >5% and high-expression alleles are associated with clinical severity of rheumatoid arthritis, scleroderma, and asthma but improved outcome from pneumonia. We completed a candidate gene association study in SLE (3195 patients and controls) to examine the relationship between two promoter polymorphisms in MIF: a -794 CATT5-8 microsatellite repeat (rs5844572), where increased repeat number leads to greater MIF expression; and a -173 G/C SNP (rs755622) that is in linkage disequilibrium with CATT7. Patients with the high-expression CATT7 allele had lower SLE incidence: OR = 0.63, P = 0.001 in Caucasians and OR = 0.46, P = 0.012 in African-Americans. Among patients with established SLE, those with serositis, nephritis, and cerebritis had reduced frequencies of low-expression MIF genotypes (CATT5) when compared with patients without end-organ involvement (P = 0.005 for serositis, P = 0.023 for nephritis, and P = 0.04 for cerebritis). Plasma MIF levels and TLR4, TLR7, and TLR9 stimulated MIF production reflected the underlying MIF genotype of the studied groups. These data suggest that MIF exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE, perhaps by contributing to enhanced clearance of infectious agents. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage [1]. We also examined the therapeutic impact of MIF antagonism in two mouse models of spontaneous SLE. In both the NZB/NZW F1 and the MRL/lpr mouse strains, anti-MIF or small molecule MIF receptor antagonism reduced functional and histological indices of glomerulonephritis, MIF-R+ leukocyte recruitment, and proinflammatory cytokine and chemokine expression [2]. A humanized anti-MIF developed from our studies has recently entered phase I clinical testing [3]. These data highlight the importance of MIF in the development of autoimmunity and support the potential clinical feasibility of pharmacologic MIF antagonism. We anticipate that MIF antagonists may be most effectively applied in those individuals who, on the basis of their genotype, manifest a MIF-dependent form of autoimmunity.

Increased macrophage migration inhibitory factor (MIF) plasma levels in acute HIV-1 infection

Considering macrophage migratory inhibitory factor (MIF) as a critical pro-inflammatory cytokine of the immune system, we evaluated plasma MIF levels in 89 HIV-infected adults. Plasma MIF levels were higher in HIV-infected than in HIV-negative individuals. Highest MIF levels were observed during acute HIV infection (AHI) whilst patients on antiretroviral therapy (ART) had lower MIF levels, regardless of ART efficacy. Our results suggest that MIF is an integral component of the cytokine storm characteristic of AHI.

Study on expression and change of peripheral blood macrophsge migration inhibitory factor in patients with acute cerebral infarction

[Objective]To explore the function of peripheral blood macrophage migration inhibitory factor (MIF) during cerebral infarction by studying the expression and change of MIF in patients with cerebral infarction.[Methods]The levels of plasma MIF were measured by enzyme linked immunosorbent assay (ELISA) and the levels of peripheral blood mononuclear cells '(PBMC) MIF mRNA were measured by real-time polymerase chain reaction (RT-PCR) in 68 patients at acute stage (1～3 days),subacute stage (10～14 days).Mean time,99 healthy persons mating cerebral infarction group in both sex and ages were measured.[Results]At acute stage,the levels of plasma M1F[(52.77 ± 25.42)ng/ml]and PBMC MIF mRNA (0.42 ± 0.37)in the patients with cerebral infarction were obviously higher than those of subacute stage[(39.20 ± 17.46)ng/ml,0.27 ± 0.29]and the healthy controls[(32.66 ± 27.92)ng/ml,0.24 ± 0.23](P ＜ 0.05).The levels of plasma MIF and PBMC MIF mRNA in the patients with cerebral infarction at subacute stage had no significant difference with those of the healthy controls (P＞ 0.05).[ConcIusions] The plasma level of MIF and the PBMC expression of MIF mRNA are in increased gradually,and then gradually drop down to normal level.Dynamic detections of the plasma level of MIF and the PBMC expression of MIF mRNA are useful for forecasting the development and prognosis of acute cerebral infarction. Key words: Cerebral infarction; Peripheral blood mononuclear cells; Macrophage migration inhibitory factor; Real-time polymerase chain reaction