Macrophage migration inhibitory factor is a cardiac-derived myocardial depressant factor

Macrophage migration inhibitory factor (MIF) is a pluripotent proinflammatory cytokine that is ubiquitously expressed in organs, including the heart. However, no specific role for MIF in modulating cardiac performance has yet been described. Therefore, we examined cardiac MIF expression in mice after LPS challenge (4 mg/kg) and tested the hypothesis that MIF is a mediator of LPS-induced cardiac dysfunction. Western blots of whole heart lysates, as well as immunohistochemistry, documented constitutive MIF protein expression in the heart. Cardiac MIF protein levels significantly decreased after LPS challenge, reaching a nadir at 12 h, and then returned to baseline by 24 h. This pattern was consistent with MIF release from cytoplasmic stores after endotoxin challenge. After release of protein, MIF mRNA levels increased 24-48 h postchallenge. To determine the functional consequences of MIF release, we treated LPS-challenged mice with anti-MIF neutralizing antibodies or isotype control antibodies. Anti-MIF-treated animals had significantly improved cardiac function, as evidenced by a significant improvement in left ventricular (LV) fractional shortening percentage at 8, 12, 24, and 48 h after endotoxin challenge. In support of these findings, perfusion of isolated beating mouse hearts (Langendorff preparation) with recombinant MIF (20 ng/ml) led to a significant decrease in both systolic and diastolic performance [LV pressure (LVP), positive and negative first derivative of LVP with respect to time, and rate of LVP rise at developed pressure of 40 mmHg]. This study demonstrates that MIF mediates LPS-induced cardiac dysfunction and suggests that MIF should be considered a pharmacological target for the treatment of cardiac dysfunction in sepsis and potentially other cardiac diseases.     

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 CATT_5–8 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.     

Macrophage migration inhibitory factor: Isolation from bovine brain

The purification of macrophage migration inhibitory factor (MIF) from bovine brain cytosol and its partial characterization are reported. A rapid and relatively simple method for MIF isolation was developed based mainly on size-exclusion chromatography on Toyopearl TSK polymer having a tendency to adsorb MIF as compared to elution of other proteins with similar molecular weights. The method gives a high yield of MIF (0.1 mg homogenous protein per g wet tissue). The retardation is conveniently utilized to achieve good separations of MIF from other proteins of similar molecular weights. The isolated protein was identified as MIF by SDS-electrophoresis, immunoblotting, sequencing of the N-terminal amino acid residues, and also by determination of keto-enol tautomerase activity that is characteristic of MIF with p-hydroxyphenylpyruvic acid as a substrate.     

Macrophage migration inhibitory factor: a regulator of MMP13 and inflammation in titanium particles-stimulated air pouch in vivo

Macrophage migration inhibitory factor (MIF) is a significant regulator of inflammatory diseases, and local inflammation plays an important role in the aseptic loosening of failed total hip arthroplasty (THA). A high-level MIF expression was found in the interfacial membrane around implants. However, the cause of increased MIF expression and the action of MIF in the process of aseptic-loosening implant is still unknown. This study is to investigate MIF expression and its upregulating effect on matrix metalloproteinases (MMPs) expression in the particles-stimulated air pouches in mice that appear to closely resemble the interfacial membranes. A total of 48 murine air pouches were divided into four groups, and were injected with PBS, titanium particles suspensions, titanium particles suspensions with neutralizing antibody of MIF, and titanium particles suspensions with normal IgG, respectively. Histological and cytokine responses were evaluated. The inflammatory reaction of air pouch membranes induced by titanium particles was significantly suppressed by neutralizing antibody. The levels of MIF protein and mRNA were significantly increased in the titanium particles-stimulated air pouch membranes compared with the control groups. So were the levels of MMP13 protein and mRNA. However, the levels of MMP13 protein and mRNA were significantly reduced by neutralizing antibody. Our study demonstrates that titanium particles can cause the air pouch membranes to increase the expression of MIF, which upregulates the production of MMP13 and induces inflammatory reaction in vivo. The results indicate that MIF may play an important role in the process of aseptic-loosening implants after THA.     

Macrophage migration inhibitory factor mediates hypoxia-induced pulmonary hypertension

Pulmonary hypertension (PH) is a devastating disease leading to progressive hypoxemia, right ventricular failure, and death. Hypoxia can play a pivotal role in PH etiology, inducing pulmonary vessel constriction and remodeling. These events lead to increased pulmonary vessel wall thickness, elevated vascular resistance and right ventricular hypertrophy. The current study examined the association of the inflammatory cytokine macrophage migration inhibitory factor (MIF) with chronic lung disease and its role in the development of hypoxia-induced PH. We found that plasma MIF in patients with primary PH or PH secondary to interstitial lung disease (ILD) was significantly higher than in the control group (P = 0.004 and 0.007, respectively). MIF involvement with hypoxia-induced fibroblast proliferation was examined in both a human cell-line and primary mouse cells from wild-type (mif ^+/+) and MIF-knockout (mif ^−/−) mice. In vitro, hypoxia-increased MIF mRNA, extracellular MIF protein accumulation and cell proliferation. Inhibition of MIF inflammatory activity reduced hypoxia-induced cell proliferation. However, hypoxia only increased proliferation of mif ^−/− cells when they were supplemented with media from mif ^+/+ cells. This growth increase was suppressed by MIF inhibition. In vivo, chronic exposure of mice to a normobaric atmosphere of 10% oxygen increased lung tissue expression of mRNA encoding MIF and accumulation of MIF in plasma. Inhibition of the MIF inflammatory active site, during hypoxic exposure, significantly reduced pulmonary vascular remodeling, cardiac hypertrophy and right ventricular systolic pressure. The data suggest that MIF plays a critical role in hypoxia-induced PH, and its inhibition may be beneficial in preventing the development and progression of the disease.     

微RNA:天然免疫的新型调节子

微RNA（microRNA,miRNA）是多种生物学过程的有效调节子,并表现为基因的定量调节。新出现的证据表明miRNA与天然免疫反应的调节有关。这种调节作用有助于维持宿主免疫反应和保护感染组织间的平衡。深入理解miRNA对天然免疫反应的调节有助于鉴定免疫调节的新靶标和建立基于miRNA的有效疗法。本综述重点总结miRNA在调节免疫细胞发育、Toll样受体和炎症细胞因子信号中的作用。     

Macrophage migration inhibitory factor is elevated in obese adolescents

Objectives: The prevalence of obesity in childhood and adolescence is continuing rising. Macrophage migration inhibitory factor (MIF) participates in inflammatory and immune responses as a pro-inflammatory cytokine. The present study aimed to investigate MIF in overweight adolescents. Methods: Seventy-nine male adolescents were enrolled. Thirty-eight were overweight according to the 90th%ile of the age-specific waist circumference. Various parameters were recorded at one visit, including body mass index. MIF was determined using multiplex immune-assay technology. Results: Overweight adolescents had increased systolic blood pressure and CRP levels. Furthermore, increased circulating MIF concentrations were observed (Median: 964.6 pg/ml, Interquartile range: 590.3-2019.4 versus Median: 562.7 pg/ml, Interquartile range: 430.6-813.7, p = 0.003). Increased MIF concentrations were associated with increased markers of inflammation and obesity. Conclusions: We demonstrated elevated MIF levels in obese adolescents. Taken together with other markers, this indicates the presence of low-grade inflammation in these young subjects, possibly representing a link between obesity and related co-morbidities.     

Macrophage migration inhibitory factor activates hypoxia-inducible factor in a p53-dependent manner

Background

Macrophage migration inhibitory factor (MIF) is not only a cytokine which has a critical role in several inflammatory conditions but also has endocrine and enzymatic functions. MIF is identified as an intracellular signaling molecule and is implicated in the process of tumor progression, and also strongly enhances neovascularization. Overexpression of MIF has been observed in tumors from various organs. MIF is one of the genes induced by hypoxia in an hypoxia-inducible factor 1 (HIF-1)-dependent manner.

Methods/Principal Findings

The effect of MIF on HIF-1 activity was investigated in human breast cancer MCF-7 and MDA-MB-231 cells, and osteosarcoma Saos-2 cells. We demonstrate that intracellular overexpression or extracellular administration of MIF enhances activation of HIF-1 under hypoxic conditions in MCF-7 cells. Mutagenesis analysis of MIF and knockdown of 53 demonstrates that the activation is not dependent on redox activity of MIF but on wild-type p53. We also indicate that the MIF receptor CD74 is involved in HIF-1 activation by MIF at least when MIF is administrated extracellularly.

Conclusion/Significance

MIF regulates HIF-1 activity in a p53-dependent manner. In addition to MIF''s potent effects on the immune system, MIF is linked to fundamental processes conferring cell proliferation, cell survival, angiogenesis, and tumor invasiveness. This functional interdependence between MIF and HIF-1α protein stabilization and transactivation activity provide a molecular mechanism for promotion of tumorigenesis by MIF.     

巨噬细胞移动抑制因子及其在动脉粥样硬化中的作用

巨噬细胞移动抑制因子（macrophage migration inhibitory factor,MIF）,其主要作用为抑制巨噬细胞的游走移动、促进巨噬细胞在炎症局部浸润、聚集、激活及分泌一些细胞因子,如IL-1、TNF—α、NO等,从而间接增强巨噬细胞的功能。巨噬细胞不仅是产生MIF的主要细胞,也是MIF作用的靶细胞,因此MIF在巨噬细胞参与调节的各种疾病尤其是动脉粥样硬化中发挥着重要作用。研究表明,血管发生动脉粥样硬化部位的MIF表达水平明显上调,且随着斑块的发展逐渐上升;相反,阻断MIF的表达则可以显著廷缓动脉粥样硬化的发撮并稳定斑块。因此,MIF在单核巨噬细胞的血管粘附、跨膜移动、内皮下聚集、泡沫细胞的形成及斑块稳定中的作用可能与动脉粥样硬化的发生和发展有密切关系。本文将主要就MIF的生理及病理生理学功能特别是其在动脉粥样硬化发病及治疗中的作用作一综述。     

Macrophage migration inhibitory factor in zinc-allergic systemic contact dermatitis

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine whose expression has been found to be critical to the generation of the antigen-specific immune response. Recent studies suggested that MIF plays a role in the initiation and maintenance of allergic disease. The aim of this study was to investigate whether MIF is involved in the pathogenesis of zinc-allergic systemic contact dermatitis. A 49-year-old Japanese woman developed facial edema, blepharedema and pruritic edematous erythema with papules over the entire body. Based of the results of a metal patch test, drug lymphocyte stimulating test and drug challenge test, diagnosis of zinc-allergic systemic contact dermatitis was made. Serum MIF and TNF-alpha levels of the patient, 20 healthy controls and other 6 patients who showed positive reaction to metal patch test were measured by an ELISA. Moreover we examined MIF production of peripheral blood mononuclear cells (PBMCs) from our patient, 3 healthy controls and other 2 patients who showed positive reaction to metal patch test at various metal concentrations. The patient's serum showed high MIF and TNF-alpha levels compared to healthy controls and other metal allergy patients. Furthermore, zinc stimulation of patient's PBMC showed higher MIF and TNF-alpha secretion compared with healthy subjects. The MIF content of 2 patients with other metal allergy was not significantly increased after metal stimulation. Our data suggest that zinc in the peripheral blood of zinc-allergic patients induce PBMCs to produce increased MIF levels, which could lead to systemic contact dermatitis.     

Macrophage migration inhibitory factor (MIF): a key player in protozoan infections

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by the pituitary gland and multiple cell types, including macrophages (Mø), dendritic cells (DC) and T-cells. Upon releases MIF modulates the expression of several inflammatory molecules, such as TNF-α, nitric oxide and cyclooxygenase 2 (COX-2). These important MIF characteristics have prompted investigators to study its role in parasite infections. Several reports have demonstrated that MIF plays either a protective or deleterious role in the immune response to different pathogens. Here, we review the role of MIF in the host defense response to some important protozoan infections.     

Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic IkappaBalpha

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine secreted by several cell types, including mononuclear and pituitary cells. It has also been shown to counteract cortisol-induced inhibition of inflammatory cytokine secretion. The purpose of this study was to determine whether MIF antagonized the effect of hydrocortisone on the NF-kappaB/IkappaB signal transduction pathway in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells. Physiological doses of hydrocortisone (50-200 ng/ml) diminished both the LPS-stimulated decrease in cytosolic IkappaBalpha levels and the subsequent increase in nuclear NF-kappaB DNA binding. In the presence of both LPS and hydrocortisone, 1 ng/ml of MIF antagonized the effects of hydrocortisone, resulting in decreased cytosolic IkappaBalpha levels (P < 0.05) and increased nuclear NF-kappaB DNA binding (P < 0.05). In the absence of hydrocortisone, MIF had no effect on LPS-induced decreases in IkappaBalpha. In the absence of LPS, MIF inhibited hydrocortisone-induced increases in IkappaBalpha (P = 0.03). Thus the mechanism by which MIF antagonizes the effect of hydrocortisone on the NF-kB/IkappaB signal transduction pathway is through inhibiting the ability of hydrocortisone to increase cytosolic IkappaBalpha.     

Macrophage migration inhibitory factor: a mediator of matrix metalloproteinase-2 production in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of bone and cartilage, which is mediated, in part, by synovial fibroblasts. Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes responsible for matrix degradation. Macrophage migration inhibitory factor (MIF) is a cytokine that induces the production of a large number of proinflammatory molecules and has an important role in the pathogenesis of RA by promoting inflammation and angiogenesis.     

Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury

We have recently demonstrated that macrophage migration inhibitory factor (MIF) is a myocardial depressant protein and that MIF mediates late, prolonged cardiac dysfunction after endotoxin challenge in mice. Because many factors, including endotoxin, have been implicated in the pathogenesis of cardiac dysfunction after burn injury, we tested the hypothesis that MIF might also be the mediator of prolonged cardiac dysfunction in this model. At 4 h after 40% total body surface area burn in anesthetized mice, serum MIF levels increased significantly compared with baseline (2.2-fold). This increase was accompanied by a significant decrease in cardiac tissue MIF levels (2.1-fold decrease compared with controls). This pattern was consistent with MIF release from preformed cytoplasmic stores in the heart and other organs. To determine whether MIF mediates cardiac dysfunction after burn injury, mice were pretreated with anti-MIF neutralizing monoclonal antibodies or isotype control antibodies. Beginning 4 h after burn injury (and continuing through 48 h), burned mice demonstrated a significantly depressed left ventricular shortening fraction of 38.6 +/- 1.8%, compared with the normal controls (56.0 +/- 2.6%). Mice treated with anti-MIF displayed an initial depression of cardiac function similar to nontreated animals but then showed rapid restoration of cardiac function with complete recovery by 24 h, which persisted for the duration of the protocol. This study is the first to demonstrate that MIF mediates late, prolonged cardiac dysfunction after burn injury and suggests that MIF blockade should be considered a therapeutic target for the treatment of burn injury.     

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion

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