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


CONCLUSIONS
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.
Dawn
Buddhadeb
B
Institute of Molecular Cardiology, Division of Cardiology, University of Louisville, Louisville, KY 40292, USA.
Xuan
Yu-Ting
YT
Guo
Yiru
Y
Rezazadeh
Arash
A
Stein
Adam B
AB
Hunt
Greg
G
Wu
Wen-Jian
WJ
Tan
Wei
W
Bolli
Roberto
R
D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D007150:Immunohistochemistry / Q000379:methods; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000032:analysis; D053613:Janus Kinase 1; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000276:immunology* / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D007527:Isoenzymes; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1