Macrophage migration inhibitory factor antagonizes pressure overload-induced cardiac hypertrophy

2013 ◽  
Vol 304 (2) ◽  
pp. H282-H293 ◽  
Author(s):  
Kiyokazu Koga ◽  
Agnes Kenessey ◽  
Kaie Ojamaa
Keyword(s):  
Signaling Pathways ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Myocardial Hypertrophy ◽  
Left Ventricular ◽  
Inhibitory Factor ◽  
Redox Activity ◽  
Macrophage Migration ◽  
Hemodynamic Stress ◽  
Hypertrophic Signaling

Macrophage migration inhibitory factor (MIF) functions as a proinflammatory cytokine when secreted from the cell, but it also exhibits antioxidant properties by virtue of its intrinsic oxidoreductase activity. Since increased production of ROS is implicated in the development of left ventricular hypertrophy, we hypothesized that the redox activity of MIF protects the myocardium when exposed to hemodynamic stress. In a mouse model of myocardial hypertrophy induced by transverse aortic coarctation (TAC) for 10 days, we showed that growth of the MIF-deficient heart was significantly greater by 32% compared with wild-type (WT) TAC hearts and that fibrosis was increased by fourfold (2.62 ± 0.2% vs. 0.6 ± 0.1%). Circulating MIF was increased in TAC animals, and expression of MIF receptor, CD74, was increased in the hypertrophic myocardium. Gene expression analysis showed a 10-fold increase ( P < 0.01) in ROS-generating mitochondrial NADPH oxidase and 2- to 3-fold reductions ( P < 0.01) in mitochondrial SOD2 and mitochondrial aconitase activities, indicating enhanced oxidative injury in the hypertrophied MIF-deficient ventricle. Hypertrophic signaling pathways showed that phosphorylation of cytosolic glycogen synthase kinase-3α was greater ( P < 0.05) at baseline in MIF-deficient hearts than in WT hearts and remained elevated after 10-day TAC. In the hemodynamically stressed MIF-deficient heart, nuclear p21CIP1 increased sevenfold ( P < 0.01), and the cytosolic increase of phospho-p21CIP1 was significantly greater than in WT TAC hearts. We conclude that MIF antagonizes myocardial hypertrophy and fibrosis in response to hemodynamic stress by maintaining a redox homeostatic phenotype and attenuating stress-induced activation of hypertrophic signaling pathways.

scholarly journals Targeting Macrophage Migration Inhibitory Factor in Acute Pancreatitis and Pancreatic Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Yongjian Wen ◽  
Wenhao Cai ◽  
Jingyu Yang ◽  
Xianghui Fu ◽  
Lohitha Putha ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Acute Pancreatitis ◽  
Signaling Pathways ◽  
Migration Inhibitory Factor ◽  
Chemokine Receptors ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Great Promise ◽  
Macrophage Migration

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine response. Intracellular MIF is involved in Toll-like receptor and inflammasome-mediated inflammatory response. Pharmacological inhibition of MIF has been shown to hold great promise in treating inflammatory diseases and cancer, including small molecule MIF inhibitors targeting the tautomerase active site of MIF and antibodies that neutralize MIF. In the current review, we discuss the role of MIF signaling pathways in inflammation and cancer and summarize the recent advances of the role of MIF in experimental and clinical exocrine pancreatic diseases. We expect to provide insights into clinical translation of MIF antagonism as a strategy for treating acute pancreatitis and pancreatic cancer.

scholarly journals The Cardioprotective Effect of Hypertonic Saline Is Associated with Inhibitory Effect on Macrophage Migration Inhibitory Factor in Sepsis

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Yi-Li Wang ◽  
Kwok-Keung Lam ◽  
Pao-Yun Cheng ◽  
Ching-Wen Kung ◽  
Shu-Ying Chen ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Hypertonic Saline ◽  
Migration Inhibitory Factor ◽  
Myocardial Contractility ◽  
Macrophage Migration Inhibitory Factor ◽  
Left Ventricular ◽  
Inhibitory Factor ◽  
Myeloperoxidase Activity ◽  
Macrophage Migration ◽  
Arterial Blood

Sepsis can cause myocardial dysfunction, which contributes to the high mortality of sepsis. Hypertonic saline (HS) has been reported to increase myocardial contractility in sepsis. In the present study, mechanisms of action of HS resuscitation (4 mL of 7.5% NaCl per kilogram) on cardiac function have been evaluated in septic rats. HS was administered 1 h after LPS (10 mg/kg, i.v.) challenge. The mean arterial blood pressure significantly decreased 4 h after LPS challenge, and septic shock was observed at the end of experiment (6 h). Posttreatment with HS prevented hypotension caused by LPS and significantly improved cardiac function, evidenced by increases in left ventricular developed pressure, mean+dP/dtand-dP/dt. The amplitude of electrical-stimulated intracellular Ca2+transient in isolated single cardiomyocytes was significantly reduced after 6 h LPS insult, which was recovered by HS. In addition, LPS resulted in significant increases in neutrophil myeloperoxidase activity, macrophage migration inhibitory factor (MIF), and NF-κB phospho-p65 protein levels in myocardium at 6 h, which were significantly attenuated by HS. In conclusion, HS improved myocardial contractility and prevented circulatory failure induced by endotoxemia, which may attribute to improvement of intracellular calcium handling process and inhibitory effects on neutrophil infiltration and MIF production in hearts.

scholarly journals Correlation between Plasma Macrophage Migration Inhibitory Factor Levels and Long-Term Prognosis in Patients with Acute Myocardial Infarction Complicated with Diabetes

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Haiyi Yu ◽  
Xinyu Wang ◽  
Xiangning Deng ◽  
Youyi Zhang ◽  
Wei Gao
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Left Ventricular ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Long Term Prognosis

Macrophage migration inhibitory factor (MIF), a widely expressed pleiotropic cytokine, is reportedly involved in several cardiovascular diseases, in addition to inflammatory diseases. Plasma MIF levels are elevated in the early phase of acute cardiac infarction. This study is aimed at investigating the correlation between plasma MIF levels and cardiac function and prognosis in patients with acute ST-segment elevation myocardial infarction (STEMI) with or without diabetes mellitus. Overall, 204 patients with STEMI who underwent emergency percutaneous coronary intervention were enrolled: 57 and 147 patients in the diabetes and nondiabetes STEMI groups, respectively. Sixty-five healthy people were selected as controls. Plasma MIF levels were measured at the time of diagnosis. Basic clinical data and echocardiographic findings within 72 h of admission were collected. Patients were followed up, and echocardiograms were reviewed at the 12-month follow-up. Plasma MIF levels were significantly higher in the diabetes and nondiabetes STEMI groups than in the control group and in patients with Killip grade≥II STEMI than in those with Killip grade I. Plasma MIF levels were negatively correlated with the left ventricular ejection fraction (LVEF) of myocardial infarction in patients with or without diabetes in the acute phase of infarction, whereas the left ventricular diastolic dysfunction (LVDD) was positively correlated. MIF levels in the nondiabetes STEMI group were positively correlated with N-terminal pro-b-type natriuretic peptide levels and were associated with LVEF and LVDD at the 12-month follow-up. The risk of adverse cardiovascular and cerebrovascular events was significantly higher in the MIF high-level group (≥52.7 ng/mL) than in the nondiabetes STEMI group 36 months after presentation. Thus, MIF levels in STEMI patients with or without diabetes can reflect acute cardiac function. In STEMI patients without diabetes, MIF levels can also indicate cardiac function and long-term prognosis at the 12-month follow-up.

scholarly journals Up-Regulation of Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Human Endometriotic Cells by Macrophage Migration Inhibitory Factor: Involvement of Novel Kinase Signaling Pathways

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3128-3137 ◽  
Author(s):  
Cédric Carli ◽  
Christine N. Metz ◽  
Yousef Al-Abed ◽  
Paul H. Naccache ◽  
Ali Akoum
Keyword(s):  
Prostaglandin E2 ◽  
Signaling Pathways ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Mapk Signaling ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Endometrial Cells ◽  
Erk Mapk ◽  
Cox 2

Cyclooxygenase (COX) is the rate-limiting enzyme in the metabolic conversion of arachidonic acid to prostaglandins (PGs), including prostaglandin E2 (PGE2), a major mediator of inflammation and angiogenesis. Herein, we report that macrophage migration inhibitory factor (MIF), a potent proinflammatory and growth-promoting factor found at elevated concentrations in the peritoneal fluid of women with endometriosis and active endometriosis lesions, acts directly on ectopic endometrial cells to stimulate the synthesis of COX-2, the inducible form of COX, and the release of PGE2. MIF treatment strongly activated p38 and ERK MAPK, and specific inhibitors of both pathways completely blocked basal and MIF-induced PGE2 synthesis. Whereas p38 inhibitors negatively affected the stimulated synthesis of COX-2 and that of PGE2, ERK inhibitors only decreased the production of PGE2. These findings show for the first time a direct role for MIF in the up-regulation of COX-2 synthesis and PGE2 secretion in ectopic endometrial cells. They further indicate that whereas p38 and ERK MAPK signaling pathways both play a significant role in the regulation of basal and MIF-induced synthesis of PGE2 by ectopic endometrial cells, only p38 kinase is involved in the regulation of COX-2 expression in these cells. This suggests that MIF acts at more than one level to stimulate the synthesis of PGE2 and triggers the coordinate activation of multiple enzymes in the biosynthesis pathway. Our data provide evidence for a novel mechanism by which MIF can induce a proinflammatory phenotype in ectopic endometrial cells, and favor the establishment of endometriosis and its related clinical symptoms.

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

2003 ◽  
Vol 285 (6) ◽  
pp. H2500-H2509 ◽  
Author(s):  
Leslie B. Garner ◽  
Monte S. Willis ◽  
Deborah L. Carlson ◽  
J. Michael DiMaio ◽  
Michael D. White ◽  
...  
Keyword(s):  
Migration Inhibitory Factor ◽  
Cardiac Dysfunction ◽  
Macrophage Migration Inhibitory Factor ◽  
Left Ventricular ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Mrna Levels ◽  
Western Blots ◽  
Endotoxin Challenge ◽  
Lps Challenge

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.

scholarly journals Macrophage Migration Inhibitory Factor Is a Molecular Determinant of the Anti-EGFR Monoclonal Antibody Cetuximab Resistance in Human Colorectal Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1430 ◽  
Author(s):  
Rosita Russo ◽  
Nunzia Matrone ◽  
Valentina Belli ◽  
Davide Ciardiello ◽  
Mariangela Valletta ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Signaling Pathways ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Combined Treatment ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Cancer Resistance ◽  
Molecular Determinant

Background: The clinical impact of the monoclonal antibody cetuximab targeting the EGFR in colorectal cancer (CRC) is widely recognized. Nevertheless, the onset of cetuximab resistance is a serious issue that limits the effectiveness of this drug in targeted therapies. Unraveling the molecular players involved in cancer resistance is the first step towards the identification of alternative signaling pathways that can be targeted to circumvent resistance mechanisms restoring the efficacy of therapeutic treatments in a tailored manner. Methods: By applying a nanoLC-MS/MS TMT isobaric labeling-based approach, we have delineated a molecular hallmark of cetuximab-resistance in CRC. Results: We identified macrophage migration inhibitory factor (MIF) as a molecular determinant capable of triggering cancer resistance in sensitive human CRC cells. Blocking the MIF axis in resistant cells by a selective MIF inhibitor restores cell sensitivity to cetuximab. The combined treatment with cetuximab and the MIF inhibitor further enhanced cell growth inhibition in CRC resistant cell lines with a synergistic effect depending on inhibition of key downstream effectors of the MAPK and AKT signaling pathways. Conclusions: Collectively, our results suggest the association of MIF signaling and its dysregulation to cetuximab drug resistance, paving the way to the development of personalized combination therapies targeting the MIF axis.

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