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 (NOS) 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 NOS and COX-2 protein expression 24 h after the PC ischemia was markedly attenuated. Conclusion: IL-6 does not modulate myocardial infarct size in naive 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. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.