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J. Biol. Chem., Vol. 278, Issue 18, 16304-16309, May 2, 2003
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From the Departments of Interleukin (IL)-6 decreases
cardiac contractility via a nitric oxide (NO)-dependent
pathway. However, mechanisms underlying IL-6-induced NO production
remain unclear. JAK2/STAT3 and ERK1/2 are two well known
signaling pathways activated by IL-6 in non-cardiac cells. However,
these IL-6-activated pathways have not been identified in adult cardiac
myocytes. In this study, we identified activation of these two pathways
during IL-6 stimulation and examined their roles in IL-6-induced NO
production and decrease in contractility of adult ventricular myocytes.
IL-6 increased phosphorylation of STAT3 (at Tyr705)
and ERK1/2 (at Tyr204) within 5 min that peaked at 15-30
min and returned to basal levels at 2 h. Phosphorylation of STAT3
was blocked by genistein, a protein tyrosine kinase inhibitor, and
AG490, a JAK2 inhibitor, but not PD98059, an ERK1/2 kinase inhibitor.
The phosphorylation of ERK1/2 was blocked by PD98059 and genistein but
not AG490. Furthermore, IL-6 enhanced de novo synthesis of
iNOS protein, increased NO production, and decreased cardiac
contractility after 2 h of incubation. These effects were blocked
by genistein and AG490 but not PD98059. We conclude that IL-6
activated independently the JAK2/STAT3 and ERK1/2 pathways, but only
JAK2/STAT3 signaling mediated the NO-associated decrease in contractility.
JAK2/STAT3, Not ERK1/2, Mediates
Interleukin-6-induced Activation of Inducible Nitric-oxide
Synthase and Decrease in Contractility of Adult Ventricular
Myocytes*
§,¶, and¶
Pharmacology and Toxicology
and ¶ Pharmaceutical Sciences, University of Arkansas for Medical
Sciences, Little Rock, Arkansas 72205
*
This study was supported in part by grants from the
Office of Naval Research and the American Heart Association/Heartland Affiliate and by NHLBI, National Institutes of Health Grant R01HL62226.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham St., MS #522-3, Little Rock, AR 72205. Tel.: 501-686-8106; Fax: 501-686-6057; E-mail: sliu@uams.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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