"Near Cure" treatment of severe acute EAE in MIF-1-deficient female and male mice with a bifunctional MHCII-derived molecular construct.

Our previous studies demonstrated increased serum levels of macrophage migration inhibitory factor (MIF-1) and its homologue, MIF-2, in males during MS progression; and that genetically high-MIF-expressing male subjects with relapsing multiple sclerosis (MS) had a significantly greater risk of conversion to progressive MS than lower-MIF-expressing males and females. However, female MS subjects with severe disease expressed higher levels of CD74, the common MIF-1/MIF-2 receptor, on blood cells. In the murine model of MS, experimental autoimmune encephalomyelitis (EAE), both male and female mice lacking MIF-1 and/or MIF-2 were clinically improved during development of moderately severe disease, thus implicating both homologs as co-pathogenic contributors. The current study using MIF-deficient mice with severe acute EAE revealed a highly significant reduction of EAE scores in MIF-1-deficient females, in contrast to only minor and delayed reduction of clinical signs in MIF-1-deficient males. However, clinical EAE scores and factor expression were strongly suppressed in males and further reduced in females after treatment of WT and MIF-1-, MIF-2- and MIF-1/2-DUAL-deficient female and male mice with a MHCII DRα1-MOG-35-55 molecular construct that competitively inhibits MIF-1 & MIF-2 signaling through CD74 as well as T cell activation. These results suggest sex-dependent differences in which the absence of the MIF-1 and/or MIF-2 genotypes may permit stronger compensatory CD74-dependent EAE-inducing responses in males than in females. However, EAE severity in both sexes could still be reduced nearly to background (a "near cure") with DRα1-MOG-35-55 blockade of compensatory MIF and CD74-dependent factors known to attract peripheral inflammatory cells into the spinal cord tissue.

Salivary alpha-1-antitrypsin and macrophage migration inhibitory factor may be potential prognostic biomarkers for oncologic treatment-induced severe oral mucositis.

AIMS: Evaluate the abundance of the selected targets, alpha-1-antitrypsin (A1AT) and macrophage migration inhibitory factor (MIF), and correlate these findings with the risk of developing severe oral mucositis (OM). MATERIALS AND METHODS: Head and neck squamous cell carcinoma (HNSCC) patients submitted to radiotherapy (RT) or chemoradiotherapy (CRT) were assessed. OM grade and pain were evaluated daily during treatment. Two protein targets, A1AT and MIF, were evaluated, using selected reaction monitoring-mass spectrometry (SRM-MS), in whole saliva, collected prior to oncologic treatment. The results obtained from the targeted proteomic analysis were correlated with OM clinical outcomes. RESULTS: A total of 27 patients were included, of whom 21 (77.8%) had locally advanced disease (clinical stage III or IV). Most patients (70.4%) received CRT. OM grades 2 (40.8%) and 3 (33.3%) were the most prevalent during RT with a mean highest reported OM-related pain of 3.22 through the visual analogue scale (VAS). The abundance of A1AT and MIF correlated significantly with severe (grades 3 or 4, p < 0.02) compared with moderate-low (grades 1 or 2, p < 0.04) OM grade. CONCLUSIONS: There is a correlation between the abundance of salivary A1AT and MIF and oncologic treatment-induced OM. The correlation of MIF expression with severe OM appears to be compatible with its physiological pro-inflammatory role. These results open up great possibilities for the use of salivary MIF and A1AT levels as prognostic markers for effective therapeutic interventions, such as photobiomodulation therapy, patient-controlled analgesia, or personalized medicaments.

Macrophage migration inhibitory factor as a therapeutic target after traumatic spinal cord injury: a systematic review.

PURPOSE: Macrophages play an important role in mediating damage after Spinal cord injury (SCI) by secreting macrophage migration inhibitory factor (MMIF) as a secondary injury mediator. We aimed to systematically review the role of MMIF as a therapeutic target after traumatic SCI. METHODS: Our systematic review has been performed according to the PRISMA 2009 Checklist. A systematic search in the scientific databases was carried out for studies published before 20 February 2019 from major databases. Two researchers independently screened titles. The risk of bias of eligible articles was assessed, and data were extracted. Finally, we systematically analyzed and interpreted related data. RESULTS: 785 papers were selected for the title and abstract screening. 12 papers were included for data extraction. Eight animal studies were of high quality and the remaining two were of medium quality. One of the two human studies was of poor quality and the other was of fair quality. MMIF as a pro-inflammatory mediator can cause increased susceptibility to glutamate-related neurotoxicity, increased nitrite production, increased ERK activation, and increased COX2/PGE2 signaling pathway activation and subsequent stimulation of CCL5-related chemotaxis. Two human studies and six animal studies demonstrated that MMIF level increases after SCI. MMIF inhibition might be a potential therapeutic target in SCI by multiple different mechanisms (6/12 studies). CONCLUSION: Most animal studies demonstrate significant neurologic improvement after administration of MMIF inhibitors, but these inhibitors have not been studied in humans yet. Further clinical trials are need to further understand MMIF inhibitor utility in acute or chronic SCI. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

MIF in kidney diseases : A story of Dr. Jekyll and Mr. Hyde.

BACKGROUND: Macrophage migration-inhibitory factor (MIF) is a cytokine best known for its proinflammatory and disease-aggravating role in a number of conditions, including atherosclerosis, autoimmune diseases, sepsis, and glomerulonephritides. OBJECTIVES: In our studies we aimed to define the role of MIF on local renal resident cells, in particular the renal epithelium. RESULTS: We have shown that MIF exerts local effects on glomerular cells, in particular the parietal epithelial cells and mesangial cells, promoting their pathological proliferation and aggravating disease course of a murine model of immune-mediated glomerulonephritis. In contrast, in a large set of animal and in vitro experiments, we have shown that in the setting of chronic kidney disease, MIF had an unexpected and potent antifibrotic and anti-inflammatory effect. This was mediated by enhanced regeneration and reduced cell-cycle arrest of tubular epithelial cells. Finally, in a combined approach using clinical studies, animal models, and in vitro experiments, we have shown that MIF is also renoprotective in the setting of acute kidney injury. In this setting, MIF-modulated programmed cell death of tubular cells and thereby reduced necroinflammation and kidney injury. CONCLUSIONS: Taken together, MIF has a dual role in kidney diseases, promoting (auto)immune glomerular diseases and limiting tubular cell injury in the setting of acute and chronic kidney diseases. These data suggest potential safety issues of systemic MIF targeted therapies, but also open new therapeutic options by targeting MIF or its analogues to tubular cells.

[Promoting migration and apoptosis of glioma cells by macrophage migration inhibitory factor].

Objective: To investigate the effect of macrophage migration inhibitory factor (MIF) on the biology of glioma U87MG and U251 cells. Methods: Silencing MIF gene expression in U87MG cells by RNA interference was monitored by Western blot. MIF low expressing U251 cells were treated at different concentrations of recombinant human MIF (rhMIF) and scratching test and flow cytometry were used to detect cell migration and apoptosis. The protein expression of bcl-2, bax, AKT, p-AKT was detected by Western blot. Results: The ability of migration and anti-apoptosis of U87MG cells silenced by siRNA decreased significantly, and the expression levels of p-AKT and anti-apoptotic protein bcl-2 also decreased; in contrast, the expression level of apoptosis protein bax increased. With increase of rhMIF treatment concentration, the expression levels of MIF protein, p-AKT and bcl-2 in U251 cells were gradually enhanced, whereas the level of apoptosis protein bax was inhibited. Conclusion: MIF promotes cell migration and inhibits apoptosis of both U87MG and U251 cells, likely through the regulation of PI3K/AKT signaling pathway.

[MIF in kidney diseases : A story of Dr. Jekyll and Mr. Hyde (German version)]. / MIF in Nierenerkrankungen : Eine Geschichte über Dr. Jekyll und Mr. Hyde.

BACKGROUND: Macrophage migration-inhibitory factor (MIF) is a cytokine best known for its proinflammatory and disease-aggravating role in a number of conditions, including atherosclerosis, autoimmune diseases, sepsis, and glomerulonephritides. OBJECTIVES: In our studies we aimed to define the role of MIF on local renal resident cells, in particular the renal epithelium. RESULTS: We have shown that MIF exerts local effects on glomerular cells, in particular the parietal epithelial cells and mesangial cells, promoting their pathological proliferation and aggravating disease course of a murine model of immune-mediated glomerulonephritis. In contrast, in a large set of animal and in vitro experiments, we have shown that in the setting of chronic kidney disease, MIF had an unexpected and potent antifibrotic and anti-inflammatory effect. This was mediated by enhanced regeneration and reduced cell-cycle arrest of tubular epithelial cells. Finally, in a combined approach using clinical studies, animal models, and in vitro experiments, we have shown that MIF is also renoprotective in the setting of acute kidney injury. In this setting, MIF-modulated programmed cell death of tubular cells and thereby reduced necroinflammation and kidney injury. CONCLUSIONS: Taken together, MIF has a dual role in kidney diseases, promoting (auto)immune glomerular diseases and limiting tubular cell injury in the setting of acute and chronic kidney diseases. These data suggest potential safety issues of systemic MIF targeted therapies, but also open new therapeutic options by targeting MIF or its analogues to tubular cells.

Association of Genetic Polymorphisms in TNF and MIF Gene with the Risk of Primary Dysmenorrhea.

Primary dysmenorrhea, which affects 90 % of adolescent girls and more than 50 % of menstruating women worldwide, is characterized by recurrent pain during menses in the absence of a detectable organic disease. The aim of this study is to assess the association between MIF -173 and TNF -308 genetic polymorphisms and the clinical features of primary dysmenorrhea. The study population comprised 154 unrelated female patients with clinical diagnosis of dysmenorrhea, and a total of 144 control subjects were recruited consecutively. The MIF -173G > C promoter polymorphism (rs755622) and TNF gene -308G > A (rs1800629) polymorphism were analyzed by polymerase chain reaction-based restriction fragment length polymorphism assay. Two fragments (268 and 97 bp) were seen when the G allele was present at position -173, and three fragments (206, 97, and 62 bp) were observed when the C allele was present. Two fragments (87 and 20 bp) were seen when G allele was present at position -308. There were statistically significant associations between age at menarche and history of back pain among dysmenorrhea patients and MIF gene -173G > C polymorphism (p = 0.003 and p = 0.042, respectively). The genotype and allele frequencies of -308G > A polymorphism showed statistically significant differences between dysmenorrhea patients and controls (p = 0.023 and p = 0.009, respectively). A high association was also observed when the patients were compared with the controls according to the GG genotype versus GA+AA genotypes (p = 0.009). The present study showed that the TNF-α -308 GG genotype may be a useful tool to predict the susceptibility of dysmenorrhea.

Elevated circulating levels of the pro-inflammatory cytokine macrophage migration inhibitory factor in individuals with acute spinal cord injury.

OBJECTIVE: To 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. DESIGN: Prospective, observational pilot study. SETTING: Academic medical center. PARTICIPANTS: Adults with acute traumatic SCI (n=18) and uninjured participants (n=18), comparable in age and sex distribution. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The 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. RESULTS: MIF 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-ß/chemokine (C-C motif) ligand 4 (P<.0015), and growth factors hepatocyte growth factor (HGF) (P<.0001) and stem cell growth factor-ß (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-ß) remained elevated throughout the study. Within individuals, MIF levels correlated with HGF (P<.018) and interleukin-16 (P<.01). CONCLUSIONS: These 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.

Compartmentalized protective and detrimental effects of endogenous macrophage migration-inhibitory factor mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion.

OBJECTIVE: Here, we aimed to clarify the role of CXC chemokine receptor (CXCR) 2 in macrophage migration-inhibitory factor (MIF)-mediated effects after myocardial ischemia and reperfusion. As a pleiotropic chemokine-like cytokine, MIF has been identified to activate multiple receptors, including CD74 and CXCR2. In models of myocardial infarction, MIF exerts both proinflammatory effects and protective effects in cardiomyocytes. Similarly, CXCR2 displays opposing effects in resident versus circulating cells. APPROACH AND RESULTS: Using bone marrow transplantation, we generated chimeric mice with Cxcr2(-/-) bone marrow-derived inflammatory cells and wild-type (wt) resident cells (wt/Cxcr2(-/-)), Cxcr2(-/-) cardiomyocytes and wt bone marrow-derived cells (Cxcr2(-/-)/wt), and wt controls reconstituted with wt bone marrow (wt/wt). All groups were treated with anti-MIF or isotype control antibody before they underwent myocardial ischemia and reperfusion. Blocking MIF increased infarction size and impaired cardiac function in wt/wt and wt/CXCR2(-/-) mice but ameliorated functional parameters in Cxcr2(-/-)/wt mice, as analyzed by echocardiography and Langendorff perfusion. Neutrophil infiltration and angiogenesis were unaltered by MIF blockade or Cxcr2 deficiency. Monocyte infiltration was blunted in wt/Cxcr2(-/-) mice and reduced by MIF blockade in wt/wt and Cxcr2(-/-)/wt mice. Furthermore, MIF blockade attenuated collagen content in all groups in a CXCR2-independent manner. CONCLUSIONS: The compartmentalized and opposing effects of MIF after myocardial ischemia and reperfusion are largely mediated by CXCR2. Although MIF confers protective effects by improving myocardial healing and function through CXCR2 in resident cells, thereby complementing paracrine effects through CD74/AMP-activated protein kinase, it exerts detrimental effects on CXCR2-bearing inflammatory cells by increasing monocyte infiltration and impairing heart function. These dichotomous findings should be considered when developing novel therapeutic strategies to treat myocardial infarction.

Protozoan-Derived Cytokine-Transgenic Macrophages Reverse Hepatic Fibrosis.

Macrophage therapy for liver fibrosis is on the cusp of meaningful clinical utility. Due to the heterogeneities of macrophages, it is urgent to develop safer macrophages with a more stable and defined phenotype for the treatment of liver fibrosis. Herein, a new macrophage-based immunotherapy using macrophages stably expressing a pivotal cytokine from Toxoplasma gondii, a parasite that infects ≈ 2 billion people is developed. It is found that Toxoplasma gondii macrophage migration inhibitory factor-transgenic macrophage (Mφtgmif) shows stable fibrinolysis and strong chemotactic capacity. Mφtgmif effectively ameliorates liver fibrosis and deactivates aHSCs by recruiting Ly6Chi macrophages via paracrine CCL2 and polarizing them into the restorative Ly6Clo macrophage through the secretion of CX3CL1. Remarkably, Mφtgmif exhibits even higher chemotactic potential, lower grade of inflammation, and better therapeutic effects than LPS/IFN-γ-treated macrophages, making macrophage-based immune therapy more efficient and safer. Mechanistically, TgMIF promotes CCL2 expression by activating the ERK/HMGB1/NF-κB pathway, and this event is associated with recruiting endogenous macrophages into the fibrosis liver. The findings do not merely identify viable immunotherapy for liver fibrosis but also suggest a therapeutic strategy based on the evolutionarily designed immunomodulator to treat human diseases by modifying the immune microenvironment.

Increased levels of macrophage migration inhibitory factor in patients with familial mediterranean Fever.

OBJECTIVE: To determine the level of macrophage migration inhibitory factor (MIF), its relationship with Mediterranean fever (MEFV) gene mutations and oxidative stress in familial Mediterranean fever (FMF). METHODS: Fifty one unrelated attack free FMF patients (24 M and 27 F, 32.8±8.7 years) and 30 healthy controls (16 M and 14 F, 32.7±7 years) were included in the study. Serum MIF, total oxidant status (TOS) and total anti-oxidant status (TAS) were studied. RESULTS: Age, sex distribution, anthropometrical indices, smoking status, serum lipids and TAS concentrations were similar between the patients and controls. However; erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), MIF, and TOS were significantly higher in the patients' group compared with healthy subjects. MIF, TOS and TAS levels were not different between patients with or without M694V mutations. CONCLUSION: We found increased concentrations of MIF in patients with FMF. Increased MIF levels were significantly correlated with oxidative stress and in regression analysis MIF concentrations were independent from the inflammatory activity as assessed by ESR and CRP. M694V mutations seem no effect on MIF and oxidative stress.

Pilot study: elevated circulating levels of the proinflammatory cytokine macrophage migration inhibitory factor in patients with chronic spinal cord injury.

OBJECTIVE: To test the hypothesis that the proinflammatory cytokine macrophage migration inhibitory factor (MIF) is elevated in the circulation of patients with chronic spinal cord injury (SCI) relative to uninjured subjects, and secondarily to identify additional immune mediators that are elevated in subjects with chronic SCI. DESIGN: Prospective, observational pilot study. SETTING: Outpatient clinic of a department of physical medicine and rehabilitation and research institute in an academic medical center. PARTICIPANTS: Individuals with chronic (>1y from initial injury) SCI (n=22) and age- and sex-matched uninjured subjects (n=19). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Plasma levels of MIF, as determined by a commercially available multiplex suspension immunoassay. The relationship between MIF levels and clinical/demographic variables was also examined. As a secondary outcome, we evaluated other cytokines, chemokines, and growth factors. RESULTS: Plasma MIF levels were significantly higher in subjects with chronic SCI than in control subjects (P<.001). Elevated MIF levels were not correlated significantly with any one clinical or demographic characteristic. Subjects with SCI also exhibited significantly higher plasma levels of monokine induced by interferon-gamma/chemokine C-X-C motif ligand 9 (P<.03), macrophage colony stimulating factor (P<.035), interleukin-3 (P<.044), and stem cell growth factor beta (SCGF-ß) (P<.016). Among subjects with SCI, the levels of SCGF-ß increased with the time from initial injury. CONCLUSIONS: These data confirm the hypothesis that MIF is elevated in subjects with chronic SCI and identify additional novel immune mediators that are also elevated in these subjects. This study suggests the importance of examining the potential functional roles of MIF and other immune factors in subjects with chronic SCI.

Migration inhibitory factor and cluster of differentiation 74-mediated dendritic cell apoptosis exacerbates acute acetaminophen-induced liver injury.

INTRODUCTION: We investigated the role of macrophage migration inhibitory factor (MIF) on dendritic cells (DC) during acetaminophen (APAP)-induced acute liver injury (ALI) in mice. METHODS: First, we randomly divided the mice into experimental (ALI model) and control groups, then intraperitoneally injected 600 mg/kg of APAP or phosphate-buffered saline, respectively. Then, we collected liver tissue and serum samples to evaluate liver inflammation using serum alanine aminotransferase level and hematoxylin and eosin (H&E) staining of liver tissues. Flow cytometry was used to identify changes in the quantity and percentage of DCs, as well as the expression of cluster of differentiation (CD) 74 and other apoptosis-related markers in the liver. Next, we randomly divided the mice into APAP-vehicles, APAP-bone marrow-derived dendritic cells (BMDCs), APAP-MIF, APAP-IgG (isotype immunoglobin G antibody) groups (four mice per group), after APAP injection, we injected control extracts, BMDCs, mouse recombinant MIF antibodies, or IgG antibodies into the tail vein. Lastly, the severity of the liver injury and the number of DCs were assessed. RESULTS: The APAP-induced ALI mice had increased hepatic MIF expression but significantly lower amounts of hepatic DCs and apoptotic DCs than healthy mice; CD74 expression on the HDCs also increased markedly. Supplementing APAP-induced ALI mice with BMDCs or MIF antibodies significantly increased the number of hepatic DCs compared with the control mice, alleviating liver damage. CONCLUSION: The MIF/CD74 signaling pathway may mediate hepatic DC apoptosis and promote liver damage.

Efficacy of Moxa-burning heat stimulating Zusanli (ST36) and Shenshu (BL23) on expressions of macrophage migration inhibitory factor and macrophage apoptosis in rabbits with adjuvant-induced arthritis.

OBJECTIVE: To evaluate the effects of moxa-burning heat stimulating acupoints Zusanli (ST36) and Shenshu (BL23) on macrophage migration inhibitory factor (MIF) and its related molecules which can provide scientific experimental basis for the clinical application of moxibustion treatment of rheumatoid arthritis (RA). METHODS: Thirty rabbits were randomly assigned to control group, RA model (established by injecting Freund's Complete Adjuvant) group (RA group) and RA model with moxibustion group [Moxa group, Zusanli (ST36) and Shenshu (BL23), 5 moxa pillars/day, 6 d × 3]. The expressions of MIF mRNA were evaluated with reverse transcription polymerase chain reaction; the apoptosis rates of macrophages were detected by erminal deoxynucleotidyl transferase-mediated dTUP nick end labeling; the expressions of related signal molecules were detected with immunohistochemical S-P method and the levels of IL-2 were detected with enzyme-linked immunosorbent assay. RESULTS: The expressions of MIF mRNA, extracellular regulated protein kinases 2, p38 mitogen-activated protein kinase and nuclear factor-κ-gene binding p65 in synovial tissue of RA group were significantly increased when compared with control group, which were lower remarkably in moxa group than those in RA group. The apoptosis rates of macrophages in RA group were significantly down-regulated as compared with the control group, which were up-regulated in moxa group compared with the RA group. The levels of IL-2 in synovial fluid from the RA group were elevated significantly as compared with that from control group, but those of the moxa group were reduced when compared with those from RA group. CONCLUSIONS: Moxibustion may simultaneously regulate the expressions of MIF and its related signaling pathways molecules, the apoptosis rate of macrophages in synovial tissue, as well as the level of inflammatory factors in synovial fluid. The results suggest that the anti-inflammatory effect of moxibustion on RA may be related to inhibit the expression of MIF in synovial tissue, the molecules of some related signaling pathways and promote the apoptosis of macrophage.

The effects of systemic steroid therapy on macrophage migration inhibitory factor concentrations in patients with nasal polyps.

OBJECTIVES: This study aimed to compare serum macrophage migration inhibitory factor concentrations before and after oral steroid therapy in nasal polyps patients, and determine whether there is a difference between pre-treatment macrophage migration inhibitory factor concentrations and healthy individuals. METHODS: The study included 24 patients with nasal polyps and 25 healthy individuals. The patient group received 1 mg/kg oral steroid. RESULTS: The mean macrophage migration inhibitory factor concentration before oral steroid therapy was 3889.79 pg/ml in the patient group and 2334.52 pg/ml in the control group. Macrophage migration inhibitory factor concentrations were statistically significantly higher in the pre-oral steroid therapy patient group than in the control group (p = 0.017). The mean pre- and post-oral steroid therapy serum macrophage migration inhibitory factor concentrations were 3889.79 pg/ml and 2451.25 pg/ml, respectively. The reduction in macrophage migration inhibitory factor concentrations was statistically significant (p = 0.010). CONCLUSION: These findings suggest that concentrations of macrophage migration inhibitory factor may play a role in the pathogenesis of nasal polyps.

Association of macrophage migration inhibitory factor gene polymorphisms with chronic periodontitis in a South Eastern Iranian population.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. It plays a vital role in immune response against the oral disease. MIF is a regulator of innate immunity, and bacterial antigens can stimulate serum level of this protein. In experimental gingivitis, the expression level of MIF increases and this increment positively correlates with oral plaque index. The single nucleotide polymorphisms in the gene encoding the MIF protein can control the function of MIF. The aim of the present study was a clarification of the associations between MIF-173 G/C, MIF 95 bp, and 189 bp insertion/deletion (I/D) polymorphisms and chronic periodontitis (CP) compared with healthy controls. MATERIALS AND METHODS: This case-control study was carried out on 210 CP patients and 100 normal subjects. MIF-173 G/C and MIF 95 bp and 189 bp I/D polymorphisms were genotyped, using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) and PCR, respectively. Allele and genotype frequencies of the variants were compared between patients and controls using Chi-square. test. The value of P < 0.05 was considered statistically significant. RESULTS: The study findings showed that MIF-173 G/C polymorphism, especially the C allele increased the risk of CP. The 95-bp I/D polymorphism was not associated with CP and the 185-bp I/D variant was not polymorphic in our population. CONCLUSION: Therefore, MIF-137 G/C variant increased the risk of CP in the South East of the Iranian population. In other words, polymorphisms in MIF gene influence clinical outcome of CP infection and influence the susceptibility to disease. Further studies with larger sample sizes and different ethnicities are required to validate our findings.

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

BACKGROUND: Despite 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. METHODS: A 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. RESULTS: Before 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). CONCLUSION: This 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.

Macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis.

Macrophage migration inhibitory factor (MIF) is originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibits the random migration of macrophages. MIF is now recognized as a multipotent cytokine involved in the regulation of immune and inf lammatory responses. In rheumatoid arthritis (RA), MIF promotes inf lammatory responses by inducing proinflammatory cytokines and tissue-degrading molecules, promoting the proliferation and survival of synovial fibroblasts, stimulating neutrophil chemotaxis, and regulating angiogenesis and osteoclast differentiation. Expression of MIF in synovial tissue and synovial fluid levels of MIF are elevated in RA patients. Specifically, MIF levels correlate with RA disease activity and high levels are associated with bone erosion. In animal models of RA, the genetic and therapeutic inhibition of MIF has been shown to control inflammation and bone destruction. Based on the role of MIF in RA pathogenesis, small molecular inhibitors targeting it or its receptor pathways could provide a new therapeutic option for RA patients.

Effect of macrophage migration inhibitory factor on corneal sensitivity after laser in situ keratomileusis in rabbit.

PURPOSE: To investigate the effect of macrophage migration inhibitory factor (MIF) on corneal sensitivity after laser in situ keratomileusis (LASIK) surgery. METHODS: New Zealand white rabbits were used in this study. A hinged corneal flap (160-µm thick) was created with a microkeratome, and -3.0 diopter excimer laser ablation was performed. Expressions of MIF mRNA in the corneal epithelial cells and surrounding inflammatory cells were analyzed using reverse transcription polymerase chain reaction at 48 hours after LASIK. After LASIK surgery, the rabbits were topically given either 1) a balanced salt solution (BSS), 2) MIF (100 ng/mL) alone, or 3) a combination of nerve growth factor (NGF, 100 ug/mL), neurotrophine-3 (NT-3, 100 ng/mL), interleukin-6 (IL-6, 5 ng/mL), and leukemia inhibitory factor (LIF, 5 ng/mL) four times a day for three days. Preoperative and postoperative corneal sensitivity at two weeks and at 10 weeks were assessed using the Cochet-Bonnet esthesiometer. RESULTS: Expression of MIF mRNA was 2.5-fold upregulated in the corneal epithelium and 1.5-fold upregulated in the surrounding inflammatory cells as compared with the control eyes. Preoperative baseline corneal sensitivity was 40.56 ± 2.36 mm. At two weeks after LASIK, corneal sensitivity was 9.17 ± 5.57 mm in the BSS treated group, 21.92 ± 2.44 mm in the MIF treated group, and 22.42 ± 1.59 mm in the neuronal growth factors-treated group (MIF vs. BSS, p < 0.0001; neuronal growth factors vs. BSS, p < 0.0001; MIF vs. neuronal growth factors, p = 0.815). At 10 weeks after LASIK, corneal sensitivity was 15.00 ± 9.65, 35.00 ± 5.48, and 29.58 ± 4.31 mm respectively (MIF vs. BSS, p = 0.0001; neuronal growth factors vs. BSS, p = 0.002; MIF vs. neuronal growth factors, p = 0.192). Treatment with MIF alone could achieve as much of an effect on recovery of corneal sensation as treatment with combination of NGF, NT-3, IL-6, and LIF. CONCLUSIONS: Topically administered MIF plays a significant role in the early recovery of corneal sensitivity after LASIK in the experimental animal model.

Macrophage migration inhibitory factor antagonist (p425) ameliorates kidney histopathological and functional changes in diabetic rats / Antagonista (p425) do fator de inibição da migração de macrófagos (MIF) melhora as alterações histopatológicas e funcionais renais em ratos diabéticos

Abstract Introduction: It is hypothesized that increased macrophage migration inhibitory factor (MIF) expression may contribute to diabetic nephropathy (DN) pathogenesis. The aim of the present study was to investigate the renal effects of MIF inhibition in a diabetic experimental model. Methods: Eighteen male Wistar rats (230 ± 20 g) were divided into three groups: 1) control, 2) diabetic (STZ, 50 mg/kg, dissolved in saline, ip), 3) diabetic + MIF antagonist (p425, 1 mg/kg per day, ip, on the 21th day, for 21 consecutive days). The treatment started since we founwd a significant increase in urine albumin excretion (UAE) rate in the diabetic rats in comparison with the control rats. The rats were kept individually in metabolic cages (8 AM-2 PM) and urine samples were collected in the 21 and 42th day. At the end, blood and tissue samples were collected for biochemical (BS, UPE, urine GAG, BUN, Cr, Na, and K) and histological analyses. Results: The results of this study showed that MIF antagonist (p425) significantly decreased urine protein and GAG excretion, urine protein/creatinine ratio, and serum BUN and Cr in the streptozotocin-induced DN in the rats. Pathological changes were significantly alleviated in the MIF antagonist (p425)-administered DN rats. Conclusion: Collectively, these data suggested that MIF antagonist (p425) was able to protect against functional and histopathological injury in the DN.

Resumo Introdução: Supõe-se que elevações da expressão do fator de inibição da migração de macrófagos (MIF) possam contribuir para a patogênese da nefropatia diabética (ND). O objetivo do presente estudo foi investigar os efeitos renais da inibição do MIF em um modelo experimental diabético. Métodos: Dezoito ratos Wistar machos (230 ± 20g) foram divididos em três grupos: 1) controle, 2) diabético (STZ 50 mg/kg dissolvida em soro fisiológico, IP), 3) diabético + antagonista do MIF (p425 1 mg/kg por dia IP no 21o dia por 21 dias consecutivos). O tratamento começou após a identificação de aumento significativo na albuminúria nos ratos diabéticos em relação aos controles. Os ratos foram mantidos individualmente em gaiolas metabólicas (8h-14h) e amostras de urina foram colhidas no 21o e no 42o dia. Ao final do estudo, amostras de sangue e tecido foram colhidas para análises bioquímicas (BS, excreção urinária de proteína, excreção urinária de GAGs, BUN, Cr, Na e K) e histológicas. Resultados: O presente estudo demonstrou que o antagonista do MIF (p425) diminuiu significativamente proteinúria, excreção urinária de GAGs , relação proteína/creatinina na urina, BUN e Cr no grupo com ND induzida por estreptozotocina. As alterações patológicas foram significativamente abrandadas nos ratos com ND que receberam antagonista do MIF (p425). Conclusão: Coletivamente, os dados sugerem que o antagonista do MIF (p425) teve efeito protetor contra lesões funcionais e histopatológicas da ND.