Effect of macrophage migration inhibitory factor on inflammatory cytokines and fibrogenic gene expression in human RPE cells

Abstract Background Although the pro-inflammatory cytokine interleukin (IL)6 has been generally regarded as “depressogenic,” recent research has started to question this assumption in light of the fact that this cytokine can also have anti-inflammatory properties. This bimodal action seems to be dependent on its concentration levels and on the concomitant presence of other pro-inflammatory cytokines. Methods We exposed a human hippocampal progenitor cell line, HPC0A07/03C, to cytokine levels described in depressed patients (IL6 5 pg/mL with IL1β 10 pg/mL or Macrophage Migration Inhibitory Factor (300 pg/mL) in healthy individuals (IL6 with IL1β, 1 pg/mL or Macrophage Migration Inhibitory Factor 10 pg/mL), as well as to the potentially anti-inflammatory, much higher concentrations of IL6 (50 000 pg/mL). Results Treatment with high concentrations of IL6 with IL1β or Macrophage Migration Inhibitory Factor (resembling depressed patients) decreases neurogenesis compared with low concentrations of the same cytokines (healthy individuals) and that this is mediated via production of, respectively, IL8 and IL1β in cell supernatant. Instead, treatment with very high, anti-inflammatory concentration of IL6 (50 000 pg/mL) together with high IL1β or Macrophage Migration Inhibitory Factor prevents decrease in neurogenesis and reduces both IL8 and IL1β. When high concentrations of both IL1β and Macrophage Migration Inhibitory Factor were used in co-treatment, as a model of treatment-resistant depression, we also demonstrated a reduction in neurogenesis and that this is mediated via a decrease in IL4; moreover, co-treatment with high IL1β and Macrophage Migration Inhibitory Factor and the very high concentration of IL6 prevented the reduction in neurogenesis and increased IL4. Conclusions Our results demonstrate that IL6 can exert both pro- and anti-inflammatory (potentially antidepressant) properties, depending on its concentrations and combinations with other inflammatory cytokines.

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Macrophage Migration Inhibitory Factor deficiency attenuates kidney Injury by downregulating cytokines via CYR61 in lupus-prone mice induced by pristane.

10.21203/rs.2.24616/v1 ◽

2020 ◽

Author(s):

Yang Tu ◽

Baoxiang Wang ◽

Suli Wang ◽

Chaofan Fan ◽

Xinyu Meng ◽

...

Keyword(s):

Lupus Nephritis ◽

Inflammatory Cytokines ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Therapeutic Option ◽

Periodic Acid ◽

Kidney Injury ◽

Macrophage Infiltration ◽

Inhibitory Factor ◽

Macrophage Migration

Abstract Background Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematous (SLE) and accounts for significant mortality and morbidity. Previous research has demonstrated that macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of lupus nephritis, but the detailed mechanism is not elucidated. The aim of this study was to explore the pathogenesis of MIF in lupus nephritis with the pristane-induced mouse model of SLE. Methods Mif-/- mice and Wild type mice in the C57BL/6 (B6) background were used to induce Lupus model by pristane. 24 hour urine and sera were collected in the sixth month and mice were sacrificed to harvest tissues. Serum ANA, anti-dsDNA antibodies, C3, urinary creatinine and albumin were detected by ELISA. Related inflammatory cytokines were detected by Bio-Plex Pro™ assays and ELISA. CYR61 mRNA expression was detected by RT-qPCR and CYR61 protein expression were detected by Western blot. Immunofluorescence was used to detect the expression of MIF, ICs and C3 deposition and related cytokines expression in the kidneys. Immunohistochemical staining was used to detect macrophage infiltration and periodic acid-Schiff (PAS) staining were used for kidney histology. The Mann-Whitney test and Student’s t test were used to compare multiple group differences. The correlation were analyzed by Spearman correlation. Results Mif -/- mice with pristane-induced SLE have less inflammatory cytokines expression in sera. The Mif-/- mice have reduced renal injury, less macrophage infiltration, CYR61 and inflammatory cytokines expression in the kidneys. MIF induced the expression of CYR61, which can induce the expression of IL-1β, IL-6 and MCP-1 in bone marrow-derived macrophages (BMDM) in a cell-based assay. Conclusions The results suggest that MIF plays an important role in kidney injury by inducing macrophages infiltration and inflammatory cytokines expression in situ. Our finding support the pathogenic contribution of high expression MIF alleles in SLE and suggest that MIF antagonism might offer an effective therapeutic option in lupus nephritis.

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BTZO-1, a Cardioprotective Agent, Reveals that Macrophage Migration Inhibitory Factor Regulates ARE-Mediated Gene Expression

Chemistry & Biology ◽

10.1016/j.chembiol.2010.10.011 ◽

2010 ◽

Vol 17 (12) ◽

pp. 1282-1294 ◽

Cited By ~ 14

Author(s):

Haruhide Kimura ◽

Yoshimi Sato ◽

Yasukazu Tajima ◽

Hirobumi Suzuki ◽

Hiroshi Yukitake ◽

...

Keyword(s):

Gene Expression ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration

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Immunopathophysiology of Juvenile Spondyloarthritis (jSpA): The “Out of the Box” View on Epigenetics, Neuroendocrine Pathways and Role of the Macrophage Migration Inhibitory Factor (MIF)

Frontiers in Medicine ◽

10.3389/fmed.2021.700982 ◽

2021 ◽

Vol 8 ◽

Author(s):

Miroslav Harjacek

Keyword(s):

Gene Expression ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Cytokine Network ◽

Long Term Outcome ◽

Nlrp3 Gene ◽

Juvenile Spondyloarthritis

Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial–entheseal complex inflammation. While the predominant role of IL17/23 axis, TNF-α, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.

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Macrophage migration inhibitory factor activates antigen-presenting dendritic cells and induces inflammatory cytokines in ulcerative colitis

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.2002.01838.x ◽

2002 ◽

Vol 128 (3) ◽

pp. 504-510 ◽

Cited By ~ 54

Author(s):

H. MURAKAMI ◽

S. M. F. AKBAR ◽

H. MATSUI ◽

N. HORIIKE ◽

M. ONJI

Keyword(s):

Ulcerative Colitis ◽

Dendritic Cells ◽

Inflammatory Cytokines ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Antigen Presenting

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Macrophage Migration Inhibitory Factor (MIF) Expression Increases during Myocardial Infarction and Supports Pro-Inflammatory Signaling in Cardiac Fibroblasts

Biomolecules ◽

10.3390/biom9020038 ◽

2019 ◽

Vol 9 (2) ◽

pp. 38 ◽

Cited By ~ 3

Author(s):

Svenja Voss ◽

Saskia Krüger ◽

Katharina Scherschel ◽

Svenja Warnke ◽

Michael Schwarzl ◽

...

Keyword(s):

Gene Expression ◽

Myocardial Infarction ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Cardiac Fibroblasts ◽

Cardiac Cells ◽

Inhibitory Factor ◽

Macrophage Migration

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto /paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival.

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