[Research progress in macrophage migration inhibitory factor (MIF) in tumor immune response].

Macrophage migration inhibitor factor (MIF), as a pro-inflammatory and oncogenic cytokine, is highly expressed in a variety of malignant tumors and recruits tumor cells or immune cells into the tumor microenvironment. MIF affects the development of tumor by altering the tumor microenvironment. In the process of tumor, MIF not only plays an anti-inflammatory role, but also promotes tumorigenesis by immune escape and immune tolerance.This is closely related to immune cells that play a role in the tumor immune response, mainly including natural killer (NK) cells, macrophages, dendritic cells, B cells, T cells and myeloid-derived suppressor cells. The article summarizes the role of MIF in tumor immune and the relationship between MIF and the development of malignant tumors, in order to provide new ideas and possible therapy for tumor treatment.

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-1ß 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.

Multifaceted interconnections between macrophage migration inhibitory factor and psychiatric disorders.

Inflammation is involved in the pathogenesis of psychiatric disorders. Many previous studies have defined the important roles of inflammatory factors in the pathogenesis, diagnosis, and treatment outcomes of psychiatric disorders. Macrophage migration inhibitory factor (MIF), a pro-inflammatory factor, has been gradually recognized to be involved in the development of neurological diseases in recent years. Our current review focuses on discussing the potential beneficial and detrimental roles of MIF in psychiatric disorders. We will provide new mechanistic insights for the development of potential diagnostic and therapeutic biomarkers based on MIF for psychiatric diseases.

Brief report: Enhanced DRα1-mMOG-35-55 treatment of severe EAE in MIF-1-deficient male mice.

Macrophage migration inhibitory factor (MIF-1) and its homologue d-dopachrome tautomerase (MIF-2) share the common CD74 receptor and function innately to enhance severity of multiple sclerosis (MS) as well as the experimental autoimmune encephalomyelitis (EAE) model for MS. We previously demonstrated that genetically high-MIF-expressing male subjects with relapsing MS had a significantly greater risk of conversion to progressive MS (PMS) than lower-MIF-expressing males. To expand on this observation, we utilized MIF-1, MIF-2, and MIF-1/2-DUAL-deficient male mice to discern if there would be a greater contribution of these inflammatory factors in EAE mice with severe vs. moderate clinical disease signs. As shown previously, mice deficient in either MIF-1 or MIF-2 each had a ∼25% reduction of moderate EAE compared to WT mice, with significant differences in disease onset and trajectory. However, EAE induction in mice deficient in both MIF-1 and MIF-2 genes did not result in a further reduction in EAE severity. This result suggests that the two MIF homologues were likely affecting the same pathogenic pathways such that each could partially compensate for the other but not in an additive or synergistic manner. However, MIF-1-KO, MIF-2-KO, and MIF-1/2-DUAL-KO mice with severe EAE did not exhibit a significant reduction in cumulative EAE scores compared with WT mice, but the MIF-1-KO and, to a lesser extent, MIF-1/2-DUAL-KO mice did show a significant reduction in daily EAE scores over the last 3 days of observation, and MIF-2-KO mice showed a more modest but still consistent reduction over the same span. Furthermore, deletion of MIF-1 resulted in a massive reduction in the expression of EAE- and Complete Freund's Adjuvant-associated inflammatory factors, suggesting delayed involvement of the MIF/CD74 axis in promoting disease expression. To further explore modulation of MIF-1 and MIF-2 effects on EAE, we treated WT mice with moderate EAE using DRα1-mMOG-35-55, an inhibitor of CD74 that blocks both MIF-1 and MIF-2 action. This treatment reduced ongoing moderate EAE severity in excess of 25%, suggesting efficient blockade of the MIF/CD74 axis in disease-enhancing pathways. Moreover, DRα1-mMOG-35-55 treatment of mice with severe EAE strongly reversed EAE- and CFA-associated expression of inflammatory cytokines and chemokines including Tnf, Ccr7, Ccr6, Ccl8, Cxcr3, and Ccl19 in MIF-deficient mouse genotypes, and also exceeded innate MIF-1 and MIF-2 EAE enhancing effects, especially in MIF-1-KO mice. These results illustrate the therapeutic potential of targeting the disease-enhancing MIF/CD74 pathway in male mice with moderate and severe EAE, with implications for treatment of high-MIF-expressing RRMS human males at risk of conversion to progressive MS as well as those that have already transitioned to PMS.

Role of MIF in coordinated expression of hepatic chemokines in patients with alcohol-associated hepatitis.

The chemokine system of ligands and receptors is implicated in the progression of alcohol-associated hepatitis (AH). Finding upstream regulators could lead to novel therapies. This study involved coordinated expression of chemokines in livers of healthy controls (HC) and patients with AH in 2 distinct cohorts of patients with various chronic liver diseases. Studies in cultured hepatocytes and in tissue-specific KO were used for mechanistic insight into a potential upstream regulator of chemokine expression in AH. Selected C-X-C chemokine members of the IL-8 chemokine family and C-C chemokine CCL20 were highly associated with AH compared with HC but not in patients with liver diseases of other etiologies (nonalcoholic fatty liver disease [NAFLD] and hepatitis C virus [HCV]). Our previous studies implicate macrophage migration inhibitory factor (MIF) as a pleiotropic cytokine/chemokine with the potential to coordinately regulate chemokine expression in AH. LPS-stimulated expression of multiple chemokines in cultured hepatocytes was dependent on MIF. Gao-binge ethanol feeding to mice induced a similar coordinated chemokine expression in livers of WT mice; this was prevented in hepatocyte-specific Mif-KO (MifΔHep) mice. This study demonstrates that patients with AH exhibit a specific, coordinately expressed chemokine signature and that hepatocyte-derived MIF might drive this inflammatory response.

Associations between salivary cytokines and periodontal and microbiological parameters in orthodontic patients.

ABSTRACT: Orthodontic treatment can lead to microbial-induced gingival inflammation and aseptic periodontal inflammations. The aim of this study was to investigate the relationship between salivary pro-inflammatory cytokines levels with gingival health status and oral microbe loads among patients undergoing orthodontic treatment.The present investigation was a cross-sectional study among a sample of 111 consecutive orthodontic patients (mean age 18.4 ±â€Š4.4 years). Clinical examinations were conducted to assess the gingival health status employing the Modified Gingival Index, Gingival Bleeding Index, and Plaque Index. Salivary microbiological assessments of total aerobic and anaerobic bacteria count, streptococci count, and lactobacilli count were undertaken. Saliva immunological assessments included Interleukin-1Beta (IL-1ß) and macrophage migration inhibitory factor (MIF) ELISA assays.The mean ±â€Šstandard deviation of salivary IL-1ß was 83.52 ±â€Š85.62 pg/ml and MIF was 4.12 ±â€Š0.96 ng/ml. Moderate positive correlations were found between salivary IL-1ß levels and total aerobic and anaerobic bacteria count, streptococci count, and lactobacilli count (r = 0.380-0.446, P < .001), and weak positive correlations between salivary MIF levels and total salivary aerobic and anaerobic bacteria counts (r = 0.249-0.306, P < .01) were observed. A positive correlation was found between salivary IL-1ß levels and Bleeding Index (r = 0.216, P < .05).The level of salivary IL-1ß positively correlates with oral bacterial load among orthodontic patients; the relationship between inflammatory cytokines and oral microflora deserved further study.

Macrophage migration inhibitory factor inhibits neutrophil apoptosis by inducing cytokine release from mononuclear cells.

The chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) is a pivotal driver of acute and chronic inflammatory conditions, cardiovascular disease, autoimmunity, and cancer. MIF modulates the early inflammatory response through various mechanisms, including regulation of neutrophil recruitment and fate, but the mechanisms and the role of the more recently described MIF homolog MIF-2 (D-dopachrome tautomerase; D-DT) are incompletely understood. Here, we show that both MIF and MIF-2/D-DT inhibit neutrophil apoptosis. This is not a direct effect, but involves the activation of mononuclear cells, which secrete CXCL8 and other prosurvival mediators to promote neutrophil survival. Individually, CXCL8 and MIF (or MIF-2) did not significantly inhibit neutrophil apoptosis, but in combination they elicited a synergistic response, promoting neutrophil survival even in the absence of mononuclear cells. The use of receptor-specific inhibitors provided evidence for a causal role of the noncognate MIF receptor CXCR2 expressed on both monocytes and neutrophils in MIF-mediated neutrophil survival. We suggest that the ability to inhibit neutrophil apoptosis contributes to the proinflammatory role ascribed to MIF, and propose that blocking the interaction between MIF and CXCR2 could be an important anti-inflammatory strategy in the early inflammatory response.

Protective Effect Against Toxoplasmosis in BALB/c Mice Vaccinated With Recombinant Toxoplasma gondii MIF, CDPK3, and 14-3-3 Protein Cocktail Vaccine.

Toxoplasma gondii can infect almost all endotherm organisms including humans and cause life-threatening toxoplasmosis in immunocompromised individuals, which leads to serious public health problems. Developing an excellent vaccine against this disease is impending. In present study, we formulated a cocktail protein vaccine including the TgMIF, TgCDPK3, and Tg14-3-3 proteins, which play critical roles in T. gondii infection. The recombinant protein vaccines were constructed and assessed by vaccination in BALB/c mice. We organized the mice in various protein combination groups of vaccines, and all mice were immunized with corresponding proteins at 0, 2, and 4 weeks. The specific protective effects of the vaccines on mice against T. gondii were analyzed by the mensuration of cytokines, serum antibodies, splenocyte proliferation assay, survival time, and parasite cyst burden of mice after the challenge. The study indicated that mice immunized with all three multicomponent proteins vaccine triggered a strong immune response with highest levels of IFN-γ production and IgG antibody compared with the other two protein combinations and controls. Moreover, there was an increase in IL-4 production and antigen-specific lymphocyte proliferation. The parasite cysts were significantly reduced (resulting in an 82.7% reduction), and survival time was longer in immunized mice with three multicomponent proteins compared with the other groups of mice. The enhanced humoral and cell-mediated immunity indicated that the protein cocktail vaccine containing three antigens provided effective protection for mice. These results indicated that recombinant TgMIF, TgCDPK3, and Tg14-3-3 multicomponent proteins were potential candidates for vaccine against toxoplasmosis.

Macrophage migration inhibitory factor (MIF) and pregnancy may impact the balance of intestinal cytokines and the development of intestinal pathology caused by Toxoplasma gondii infection.

Toxoplasma gondii (T. gondii) is an intracellular parasite responsible for causing toxoplasmosis. When infection occurs during pregnancy, it can produce severe congenital infection with ocular and neurologic damage to the infant. From the oral infection parasite reaches the intestine, causing inflammatory response, damage in tissue architecture and systemic dissemination. Macrophage migration inhibition factor (MIF) is a cytokine secreted from both immune and non-immune cells, including gut epithelial cells. MIF is described to promote inflammatory responses, to be associated in colitis pathogenesis and also to play role in maintaining the intestinal barrier. The aim of the present study was to evaluate the influence of the pregnancy and MIF deficiency on T. gondii infection in the intestinal microenvironment and to address how these factors can impact on the intestinal architecture and local cytokine profile. For this purpose, small intestine of pregnant and non-pregnant C57BL/6 MIF deficient mice (MIF-/-) and Wild-type (WT) orally infected with 5 cysts of ME-49 strain of T. gondii were collected on day 8th of infection. Intestines were processed for morphological and morphometric analyses, parasite quantification and for cytokines mensuration. Our results showed that the absence of MIF and pregnancy caused an increase in T. gondii infection index. T. gondii immunolocalization demonstrated that segments preferentially infected with T. gondii were duodenum and ileum. The infection caused a reduction in the size of the intestinal villi, whereas, infection associated with pregnancy caused an increase in villi size due to edema caused by the infection. Also, the goblet cell number was increased in the ileum of MIF-/- mice, when compared to the corresponding WT group. Analyses of cytokine production in the small intestine showed that MIF was up regulated in the gut of pregnant WT mice due to infection. Also, infection provoked an intense Th1 response that was more exacerbated in pregnant MIF-/- mice. We also detected that the Th2/Treg response was more pronounced in MIF-/- mice. Altogether, our results demonstrated that pregnancy and MIF deficiency interferes in the balance of the intestinal cytokines and favors a Th1-immflamatory profile, which in turn, impact in the development of pathology caused by T. gondii infection in the intestinal microenvironment.

Role of MIF Cytokine/CD74 Receptor Pathway in Protecting Against Injury and Promoting Repair.

Wound healing after an injury is essential for life. An in-depth understanding of the healing process is necessary to ultimately improve the currently limited treatment options for patients suffering as a result of damage to various organs and tissues. Injuries, even the most minor, trigger an inflammatory response that protects the host and activates repair pathways. In recent years, substantial progress has been made in delineating the mechanisms by which inflammatory cytokines and their receptors facilitate tissue repair and regeneration. This mini review focuses on emerging literature on the role of the cytokine macrophage migration inhibitory factor (MIF) and its cell membrane receptor CD74, in protecting against injury and promoting healing in different parts of the body.

Inhibition of macrophage migration inhibitory factor prevents thyroid dysfunction in pregnant rats with acute pancreatitis.

Acute pancreatitis during pregnancy (APIP) rarely occurs but may lead to preterm delivery and be associated with high fetal mortality. Macrophage migration inhibitory factor (MIF) participates in various inflammatory diseases as a pro-inflammatory cytokine. In this study, we aimed to explore the effects of (S, R)-3-(4-hydroxyphenyl)-4, 5dihydro-5-isoxazole acetic methyl ester (ISO-1), an inhibitor of MIF, on maternal thyroid injury associated with APIP and its potential mechanisms in a pregnant rat model. APIP model was induced by retrograde injection of sodium taurocholate. ISO-1 was injected intraperitoneally 30 min before model establishment. The severity of pancreatitis was assessed by levels of tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL-6 of maternal serum as well as histopathological score. Thyroid injury was determined by free triiodothyronine (FT3), free tetraiodothyronine (FT4) and thyroid histopathological score. Levels of MIF in maternal serum and the expression of MIF, CD68, CD3 and intercellular cell adhesion molecule-1 (ICAM-1) as well as oxidative stress status in maternal thyroid tissues were detected. Ultrastructure of maternal thyroid tissues was observed by transmission electron microscope. Thyroid injuries occurred in APIP and the lesions were attenuated with the pretreatment of ISO-1. Moreover, ISO-1 reduced the expression of MIF, attenuated the activations of CD68, CD3, ICAM-1 while improved oxidative stress status in maternal thyroid. Our research suggested a protective role of ISO-1 on thyroid injury and endocrine disorder during APIP, which may be associated with the inhibition of biological functions of MIF.

Glioblastoma Myeloid-Derived Suppressor Cell Subsets Express Differential Macrophage Migration Inhibitory Factor Receptor Profiles That Can Be Targeted to Reduce Immune Suppression.

The application of tumor immunotherapy to glioblastoma (GBM) is limited by an unprecedented degree of immune suppression due to factors that include high numbers of immune suppressive myeloid cells, the blood brain barrier, and T cell sequestration to the bone marrow. We previously identified an increase in immune suppressive myeloid-derived suppressor cells (MDSCs) in GBM patients, which correlated with poor prognosis and was dependent on macrophage migration inhibitory factor (MIF). Here we examine the MIF signaling axis in detail in murine MDSC models, GBM-educated MDSCs and human GBM. We found that the monocytic subset of MDSCs (M-MDSCs) expressed high levels of the MIF cognate receptor CD74 and was localized in the tumor microenvironment. In contrast, granulocytic MDSCs (G-MDSCs) expressed high levels of the MIF non-cognate receptor CXCR2 and showed minimal accumulation in the tumor microenvironment. Furthermore, targeting M-MDSCs with Ibudilast, a brain penetrant MIF-CD74 interaction inhibitor, reduced MDSC function and enhanced CD8 T cell activity in the tumor microenvironment. These findings demonstrate the MDSC subsets differentially express MIF receptors and may be leveraged for specific MDSC targeting.

Lenalidomide and pomalidomide potently interfere with induction of myeloid-derived suppressor cells in multiple myeloma.

An increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM. Using a transwell co-culture system, four of nine examined human myeloma-derived cell lines (HMCLs) were potent in inducing monocytic (M)-MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of C-C motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds, such as lenalidomide (LEN) and pomalidomide (POM), were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of cereblon (CRBN)-dependent and -independent downregulation of CCL5 and MIF in myeloma cells; and downregulation of C-C motif chemokine receptor 5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. In the present study of the molecular mechanisms underlying MDSC induction, we identified a novel effect of LEN and POM of inhibiting MDSC induction via overlapping regulatory effects in myeloma cells and normal PBMCs.

Identification and immunologic property of macrophage migration inhibitory factor (MIF) in grass carp (Ctenopharynogodon idella).

Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, plays an important regulatory role in the activation of T cells induced by mitogenic or antigenic stimuli. However, the immunologic property of MIF in freshwater fish is limitedly known by now. In the present study, MIF gene was identified in grass carp. Bioinformatics analysis revealed that the molecular weight of grass carp MIF protein was 12.377 kDa and it could also bind to CD74. MIF gene was predominantly expressed in immune tissues including spleen and head kidney, then liver, skin, gill, intestine and blood, while a relative low level expression in heart, brain, fat and red muscle. The predicted receptor and tissues distribution of MIF implied the immunologic activity of grass carp MIF. Then grass carp MIF antigen and the polyclonal antibodies against it were prepared. Using cadmium as an immunosuppressive agent, MIF expression in spleen and head kidney was depressed in a dose-dependent manner with cadmium consumption. On the same time, white blood cell count decrease displayed a similar pattern with MIF expression, which suggested a possible positive correlation between MIF and white blood cell count. Thereafter, MIF enhanced the viability of grass carp peripheral blood leukocytes and inhibited cell apoptosis with depressed reactive oxygen species production in vitro. In addition, recombinant grass carp MIF promoted tumor necrosis factor-alpha (TNF-α), interleukin 1ß (IL1ß) and interleukin 6 (IL6) secretion from peripheral blood leukocytes. These results indicated the immunologic property of grass carp MIF.

Immune modulation by the macrophage migration inhibitory factor (MIF) family: D-dopachrome tautomerase (DDT) is not (always) a backup system.

Human macrophage migration inhibition factor (MIF) is a protein with cytokine and chemokine properties that regulates a diverse range of physiological functions related to innate immunity and inflammation. Most research has focused on the role of MIF in different inflammatory diseases. D-dopachrome tautomerase (DDT), a different molecule with structural similarities to MIF, which shares receptors and biological functions, has recently been reported, but little is known about its roles and mechanisms. In this review, we sought to understand the similarities and differences between these molecules by summarizing what is known about their different structures, receptors and mechanisms regulating their expression and biological activities with an emphasis on immunological aspects.

Characterization and expression of macrophage migration inhibitory factor (mif) in Chinese sturgeon (Acipenser sinensis).

The Chinese sturgeon (Acipenser sinensis) is one of the critically endangered aquatic species in China. It is also among the oldest extant actinopterygian fish species. To advance the characterization of the Chinese sturgeon immune system, we identified the gene encoding the macrophage migration inhibitory factor (MIF), a multifunctional cytokine that contributes to both innate and adaptive immune responses. Molecular and phylogenic analysis indicates the Chinese sturgeon (cs) MIF share a high degree of structural conservation with other MIF sequences and is closely related to other bony fish MIF. At steady state, cs-mif gene is expressed at relatively high levels in the brain, and to a lesser but significant level in liver, spleen, kidney, gut and skin. The spatial expression patterns determined by in situ hybridization indicates a preferential distribution of cs-mif transcripts in the cerebral cortex, the gut epithelium, hematopoietic tissues of kidney, spleen and liver parenchyma, and skin epidermis. Marked increase of cs-mif gene expression was induced by lipopolysaccharide (LPS) stimulation and Aeromonas hydrophila infection in all tested tissues. Furthermore, higher cs-mif transcript levels were detected in the liver, spleen, kidney, gut and skin during stress response resulting from hyperthermia. These results are not only consistent with the expected role of cs-mif gene in innate immunity but also suggest a potential role of this gene in stress response to hyperthermia in the Chinese sturgeon.

Secretome-Mediated Interactions with Intestinal Epithelial Cells: A Role for Secretome Components from Lactobacillus rhamnosus R0011 in the Attenuation of Salmonella enterica Serovar Typhimurium Secretome and TNF-α-Induced Proinflammatory Responses.

Recent evidence suggests that lactic acid bacteria communicate with host cells via secretome components to influence immune responses but less is known about gut-pathogen secretomes, impact of lactic acid bacteria secretomes on host-pathogen interactions, and the mechanisms underlying these interactions. Genome-wide microarrays and cytokine profiling were used to interrogate the impact of the Lactobacillus rhamnosus R0011 secretome (LrS) on TNF-α and Salmonella enterica subsp. enterica serovar Typhimurium secretome (STS)-induced outcomes in human intestinal epithelial cells. The LrS attenuated both TNF-α- and STS-induced gene expression involved in NF-κB and MAPK activation, as well as expression of genes involved in other immune-related signaling pathways. Specifically, the LrS induced the expression of dual specificity phosphatase 1 (DUSP1), activating transcription factor 3 (ATF3), and tribbles pseudokinase 3 (TRIB3), negative regulators of innate immune signaling, in HT-29 intestinal epithelial cells challenged with TNF-α or STS. TNF-α- and STS-induced acetylation of H3 and H4 histones was attenuated by the LrS, as was the production of TNF-α- and STS-induced proinflammatory cytokines and chemokines. Interestingly, the LrS induced production of macrophage migration inhibitory factor (MIF), a cytokine involved in host-microbe interactions at the gut interface. We propose that the LrS attenuates proinflammatory mediator expression through increased transcription of negative regulators of innate immune activity and changes in global H3 and H4 histone acetylation. To our knowledge, these findings provide novel insights into the complex multifaceted mechanisms of action behind secretome-mediated interdomain communication at the gut-mucosal interface.

Contribution of astrocytes and macrophage migration inhibitory factor to immune-mediated canine encephalitis caused by the distemper virus.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that is produced by many cell types in situations of homeostasis or disease. One of its functions is to act as a proinflammatory molecule. In humans, several studies have shown that MIF levels become elevated in the serum, urine, cerebrospinal fluid and tissues of patients with chronic inflammatory diseases (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, sepsis, atheromas, diabetes and cancer). In dogs, distemper is a viral infectious condition that may lead to demyelination and inflammation in the central nervous system (CNS). In addition to the action of the virus, the inflammatory process may give rise to lesions in the white matter. Therefore, the objectives of the present study were to evaluate the role of MIF in the encephalitis that the canine distemper virus causes and to compare this with immunodetection of major histocompatibility complex-II (MHC-II), CD3 T lymphocytes, MMP-9 and glial fibrillary acidic protein (GFAP; astrocytes) in demyelinated areas of the encephalon, in order to ascertain whether these findings might be related to the severity of the encephalic lesions. To this end, a retrospective study on archived paraffinized blocks was conducted, in which 21 encephala from dogs that had been naturally infected with the canine distemper virus (infected group) and five from dogs that had been free from systemic or CNS-affecting diseases (control group) were used. In the immunohistochemical analysis on the samples, the degree of marking by GFAP, MHC-II, MMP-9 and MIF was greater in the demyelinated areas and in the adjacent neuropil, and this was seen particularly in astrocytes. Detection of CD3 was limited to perivascular cuffs. In areas of liquefactive necrosis, Gitter cells were positive for MMP-9, MIF and MHC-II. Hence, it was concluded that activated astrocytes influenced the afflux of T lymphocytes to the encephalon (encephalitis). In the more advanced phases, activated phagocytes in the areas of liquefactive necrosis (Gitter cells) continued to produce inflammatory mediators even after the astrocytes in these localities had died, thereby worsening the encephalic lesions. Distemper virus-activated astrocytes and microglia produce MIF that results in proinflammatory stimulus on glial cells and brain-infiltrating leukocytes. Therefore, the effect of the inflammatory response is potentiated on the neuropil, resulting in neurological clinical signs.

The Role of Macrophage Migration Inhibitory Factor in Alzheimer's Disease: Conventionally Pathogenetic or Unconventionally Protective?

Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer's disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD.

Purification of Antibodies Against Entamoeba histolytica MIF and Their Use in Analyzing Human and Mouse Samples.

Macrophage migration inhibitory factor (MIF) is a proinflammatory and proproliferative cytokine expressed in humans. MIF homologs also exist in many pathogenic protozoans, including Entamoeba, Plasmodium, Toxoplasma, and Leishmania. Production of antibodies against parasite proteins allows for the generation of assays to measure and visualize parasite infection within hosts. In this chapter, we describe how to specifically purify antibodies against Entamoeba histolytica MIF (EhMIF), and subsequently use anti-EhMIF antibodies for ELISA on mouse and human samples and for immunohistochemistry on human tissue. These methods can be applied to any protein for high-quality antibody purification.