© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Macrophage migration inhibitory factor as a redox-sensitive cytokine in cardiac myocytes
aDivision of Cardiology, Jichi Medical School, Tochigi, Japan
bDivision of Organ Replacement Research, Jichi Medical School, Tochigi, Japan
cCentral Research Institute, School of Medicine, Hokkaido University, Sapporo, Japan
dDivision of Functional Genomics, Jichi Medical School, Tochigi, Japan
eSapporo Immunodiagnostic Laboratory, Sapporo, Japan
* Corresponding author. Division of Cardiology, Jichi Medical School, Minamikawachi-machi, Tochigi 329-04, Japan. Tel.: +81-285-58-7344; fax: +81-285-44-5317 masafumi{at}jichi.ac.jp
Objective: Macrophage migration inhibitory factor (MIF), which plays a pivotal role in the control of inflammatory responses, was first characterized as a T-cell cytokine, but later was also found as a pituitary peptide released in response to infection and stress. However, MIF’s role and expression in the myocardium has never been reported. The goal of this study is to examine MIF in the myocardium. Methods and results: MIF protein and mRNA levels were assayed using enzyme-linked immunosorbent assay (ELISA) and reverse transcription–polymerase chain reaction (RT–PCR), respectively. Increased MIF concentrations were detected in the sera of patients with acute myocardial infarction (AMI). In cultured rat cardiac myocytes, significant amounts of MIF were produced in response to hypoxia and hydrogen peroxide (H2O2), but not to angiotensin II, endothelin-1, interleukin-1β (IL-1β) or tumor necrosis factor 
(TNF). H2O2-induced MIF production increased in a time- and dose-dependent manner and was completely abolished in the presence of catalase. H2O2 also induced MIF mRNA expression. The H2O2-induced MIF production was completely inhibited by the protein kinase C (PKC) inhibitor GF109203X, partially inhibited by the tyrosine kinase inhibitor herbimycin A, and uninhibited by calcium chelation or phorbol ester-sensitive PKC down-regulation. This suggests that H2O2-induced MIF production is mediated by an atypical PKC isoform. DNA microarray analysis revealed that 52 genes were preferentially expressed in response to MIF. Of these, the MIF-induced expression of both glutathione S-transferase (GST) and lipopolysaccharide-induced CXC chemokine (LIX) mRNAs was confirmed using RT–PCR analysis. Conclusion: The present results suggest that MIF is expressed by the myocardium in response to redox stress and may play a role in the pathogenesis of myocardial ischemia.
KEYWORDS Cytokines; Hypoxia/anoxia; Reperfusion; Ischemia
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