IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2

Cardiovasc Res. 2004 Oct 1;64(1):61-71. doi: 10.1016/j.cardiores.2004.05.011.


Objective: We sought to determine whether interleukin (IL)-6 modulates myocardial infarction or the late phase of preconditioning (PC).

Methods: Wild-type and IL-6(-/-) mice underwent a 30-min coronary occlusion followed by 24 h of reperfusion with or without six cycles of coronary occlusion/reperfusion 24 h earlier. Myocardial IL-6 protein expression, activation of Janus kinase (JAK) 1 and JAK2, and signal transducers and activators of transcription (STAT) 1 and STAT3 after ischemic PC protocol were examined. The expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 was determined 24 h after the PC ischemia.

Results: In preconditioned wild-type mice, infarct size was reduced from 60.5+/-2.6% of the risk region to 33.5+/-3.6%, indicating a late PC effect. In nonpreconditioned IL-6(-/-) mice, infarct size was similar to that observed in wild-type mice (59.9+/-3.8%), indicating that the deletion of IL-6 has no effect on infarct size. However, in preconditioned IL-6(-/-) mice, infarct size was not reduced (65.1+/-3.1%), indicating that the infarct-sparing effect was completely abrogated. Ischemic PC increased the expression of IL-6 in the cytoplasm of cardiomyocytes in the ischemic/reperfused zone. In IL-6(-/-) mice, the ischemic PC-induced activation of JAK1 and JAK2 and STAT1 and STAT3 was significantly reduced, and the increase in iNOS and COX-2 protein expression 24 h after the PC ischemia was markedly attenuated.

Conclusion: IL-6 does not modulate myocardial infarct size in naïve myocardium. However, following a PC stimulus, IL-6 is obligatorily required for the activation of the JAK-STAT pathway, the ensuing upregulation of iNOS and COX-2 (co-mediators of late PC), and the development of a cardioprotective phenotype.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Nucleus / chemistry
  • Cyclooxygenase 2
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • Immunohistochemistry / methods
  • Interleukin-6 / analysis
  • Interleukin-6 / genetics
  • Interleukin-6 / physiology*
  • Ischemic Preconditioning, Myocardial*
  • Isoenzymes / analysis
  • Janus Kinase 1
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Microscopy, Confocal
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / prevention & control
  • Myocardial Reperfusion Injury / immunology*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardium / chemistry
  • Myocardium / immunology
  • Myocardium / metabolism
  • Myocytes, Cardiac / chemistry
  • Myocytes, Cardiac / immunology
  • Myocytes, Cardiac / metabolism
  • Nitric Oxide Synthase / analysis
  • Nitric Oxide Synthase Type II
  • Prostaglandin-Endoperoxide Synthases / analysis
  • Protein-Tyrosine Kinases / metabolism*
  • STAT1 Transcription Factor
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism*


  • DNA-Binding Proteins
  • Interleukin-6
  • Isoenzymes
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Protein-Tyrosine Kinases
  • Jak1 protein, mouse
  • Janus Kinase 1