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.

Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury

2005 ◽  
Vol 288 (2) ◽  
pp. H795-H804 ◽  
Author(s):  
Monte S. Willis ◽  
Deborah L. Carlson ◽  
J. Michael DiMaio ◽  
Michael D. White ◽  
D. Jean White ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Migration Inhibitory Factor ◽  
Cardiac Dysfunction ◽  
Macrophage Migration Inhibitory Factor ◽  
Burn Injury ◽  
Total Body Surface Area ◽  
Left Ventricular ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Endotoxin Challenge

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

scholarly journals Knockdown of Macrophage Migration Inhibitory Factor Disrupts Adipogenesis in 3T3-L1 Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6037-6042 ◽  
Author(s):  
Daisuke Ikeda ◽  
Shinji Sakaue ◽  
Mitsunori Kamigaki ◽  
Hiroshi Ohira ◽  
Naofumi Itoh ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Clonal Expansion ◽  
Cell Number ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Mrna Levels ◽  
Transfected Cells ◽  
Mitotic Clonal Expansion

Obesity is a condition in which adipose tissue mass is expanded. Increases in both adipocyte size and number contribute to enlargement of adipose tissue. The increase in cell number is thought to be caused by proliferation and differentiation of preadipocytes. Macrophage migration inhibitory factor (MIF) is expressed in adipocytes, and intracellular MIF content is increased during adipogenesis. Therefore, we hypothesized that MIF is associated with adipocyte biology during adipogenesis and focused on the influence of MIF on adipogenesis. To examine the effects of MIF on adipocytes, MIF expression in 3T3-L1 preadipocytes was inhibited by RNA interference, and cell differentiation was induced by standard procedures. The triglyceride content of MIF small interfering RNA (siRNA)-transfected 3T3-L1 cells was smaller than that of nonspecific siRNA-transfected cells. In addition, MIF knockdown apparently abrogated increases in adiponectin mRNA levels during differentiation. Gene expression of peroxisome proliferator-activated receptor (PPAR)γ, CCAAT/enhancer binding protein (C/EBP)α, and C/EBPδ decreased with MIF siRNA transfection, but C/EBPβ expression increased. Cell number and incorporation of 5-bromo-2-deoxyuridine into cells decreased from 1–3 d and from 14–20 h, respectively, after induction of differentiation in MIF siRNA-transfected cells, thus suggesting that MIF siRNA inhibits mitotic clonal expansion. Taken together, these results indicated that MIF regulates differentiation of 3T3-L1 preadipocytes, at least partially, through inhibition of mitotic clonal expansion and/or C/EBPδ expression.

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 A genetic role for macrophage migration inhibitory factor (MIF) in Epinephelus awoara infected with Vibrio parahaemolyticus

2016 ◽  
Vol 14 (3) ◽  
pp. 184-189
Author(s):  
Xiaojin Xu ◽  
Benhong Sang ◽  
Gang Luo
Keyword(s):  
Migration Inhibitory Factor ◽  
Vibrio Parahaemolyticus ◽  
Macrophage Migration Inhibitory Factor ◽  
Head Kidney ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Mrna Levels ◽  
Tissue Levels ◽  
Tnf Α ◽  
Epinephelus Awoara

Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine in immuno-inflammatory diseases. For the first time, we examined the expression of MIF in Epinephelus awoara ( E. awoara). MIF expressions have been detected in the head kidney, spleen, liver, brain, intestine, gill, heart, stomach, and muscle of E. awoara infected with Vibrio parahaemolyticus. The mRNA levels observed in infected groupers were higher than those in healthy groupers. MIF, tumor necrosis factor-α (TNF-α), and interleukin-1 (IL-1) tissue levels have been measured by ELISA. A significant increase in MIF, TNF-α, and IL-1 tissue levels have been found in the treatment groups compared with those in controls. MIF, TNF-α and IL-1 tissue levels in the spleen, head kidney, intestine, and liver of E. awoara during the challenge trial with V. parahaemolyticus were significantly higher than those in controls. There was evidence of functions of MIF in a positive feedback loop with TNF-α and IL-1 that could perpetuate the inflammatory process in grouper infected with V. parahaemolyticus. In conclusion, these results indicated that MIF was related to pathogen-induced immune response.

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.

Null mutation in macrophage migration inhibitory factor prevents muscle cell loss and fibrosis in partial bladder outlet obstruction

2006 ◽  
Vol 291 (6) ◽  
pp. F1343-F1353 ◽  
Author(s):  
John A. Taylor ◽  
Qing Zhu ◽  
Brian Irwin ◽  
Yazeed Maghaydah ◽  
John Tsimikas ◽  
...  
Keyword(s):  
Migration Inhibitory Factor ◽  
Bladder Outlet Obstruction ◽  
Macrophage Migration Inhibitory Factor ◽  
Outlet Obstruction ◽  
Inhibitory Factor ◽  
Detrusor Muscle ◽  
Detrusor Underactivity ◽  
Macrophage Migration ◽  
Mrna Levels ◽  
Partial Bladder Outlet Obstruction

Idiopathic detrusor underactivity (DU) and detrusor decompensation which develops following partial bladder outlet obstruction (pBOO) are both associated with smooth muscle degeneration and fibrosis. Macrophage migration inhibitory factor (MIF), an important mediator of bladder inflammation, has been shown to promote fibroblast survival and muscle death in other tissues. We evaluated the hypothesis that MIF has similar actions in the bladder by studying detrusor responses to pBOO or sham surgery in anesthetized female mice rendered null for the mif gene (MIF KO) and in wild-type (WT) controls, all killed 3 wk after surgery. WT mice revealed intense MIF immunoreactivity in urothelial cells which decreased, without change in overall mif mRNA levels. Stereologically sound quantitative morphometric measurements were performed in the middetrusor region of each bladder. MIF KO bladders were normal in appearance, yet were 30–40% heavier, with increased middetrusor collagen and muscle, compared with WT controls. In WT mice, pBOO increased the collagen-to-muscle ratio 1.9-fold and middetrusor collagen 1.8-fold, while nucleated muscle counts were 22% lower. In MIF KO mice, by contrast, pBOO had no significant effect on any of these parameters. In primary bladder muscle cultures, treatment with rMIF protein increased TUNEL staining, raising the proportion of early and late apoptotic cells on flow cytometry. Our studies implicate MIF in the sequence of events leading to detrusor muscle loss and fibrosis in obstruction. They raise the possibility that strategies designed to antagonize MIF synthesis, release, or biological activity could prevent or delay DU and urinary retention.

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 Macrophage Migration Inhibitory Factor Inhibition Is Deleterious for High-Fat Diet-Induced Cardiac Dysfunction

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e58718 ◽  
Author(s):  
Aurore Palud ◽  
Camille Marciniak ◽  
David Montaigne ◽  
Xavier Marechal ◽  
Caroline Ballot ◽  
...  
Keyword(s):  
Migration Inhibitory Factor ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
High Fat
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