title: Macrophage migration inhibitory factor as a redox-sensitive cytokine in cardiac myocytes.
abstract: 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.
  
  
  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 (H(2)O(2)), but not to angiotensin II, endothelin-1, interleukin-1beta (IL-1beta) or tumor necrosis factor alpha (TNFalpha). H(2)O(2)-induced MIF production increased in a time- and dose-dependent manner and was completely abolished in the presence of catalase. H(2)O(2) also induced MIF mRNA expression. The H(2)O(2)-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 H(2)O(2)-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cardiology, Jichi Medical School, Tochigi, Japan. masafumi@jichi.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: J
authors.initials: J
authors.lastname: Nishihira
authors.forename: M
authors.initials: M
authors.lastname: Shimpo
authors.forename: Y
authors.initials: Y
authors.lastname: Mizue
authors.forename: S
authors.initials: S
authors.lastname: Ueno
authors.forename: H
authors.initials: H
authors.lastname: Mano
authors.forename: E
authors.initials: E
authors.lastname: Kobayashi
authors.forename: U
authors.initials: U
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Shimada
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016227:Benzoquinones; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008263:Macrophage Migration-Inhibitory Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017828:Rifabutin / Q000031:analogs & derivatives
chemical_list: D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007211:Indoles; D047029:Lactams, Macrocyclic; D008263:Macrophage Migration-Inhibitory Factors; D008301:Maleimides; D011809:Quinones; D012333:RNA, Messenger; D017828:Rifabutin; C020754:herbimycin; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; C070515:bisindolylmaleimide I