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J. Biol. Chem., Vol. 278, Issue 23, 21070-21075, June 6, 2003

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Interleukin-6 Family of Cytokines Mediates Isoproterenol-induced Delayed STAT3 Activation in Mouse Heart^*

Feng Yin , Ping Li , Ming Zheng , Li Chen , Qi Xu , Kai Chen , Yong-yu Wang , You-yi Zhang  ¶ and Chide Han 

From the Institute of Vascular Medicine, Peking University Third Hospital and The Reference Laboratory of Education Ministry on Molecular Cardiology and Institute of Cardiovascular Science, Peking University Health Science Center, Beijing 100083, People's Republic of China

This study was aimed to determine whether -adrenergic receptor (-AR) stimulated by isoproterenol (ISO) activates signal transducers and activators of transcription (STAT) in mouse heart and, if so, to examine the underlying mechanism. We found that treatment of adult male mice by ISO (15 mg/kg body weight, intraperitoneal) caused a delayed STAT3 activation (at 60–120 min), which was fully abolished by -AR antagonist, propranolol. ISO-induced phosphorylation of STAT3 was markedly enhanced by phosphodiesterase inhibitor amrinone, indicating that cAMP is critically involved in -AR-mediated STAT3 activation. In addition, -AR stimulation significantly increased gene expression of interleukin-6 (IL-6) family of cytokines (IL-6, leukemia inhibitory factor, ciliary neurotrophic factor, and cardiotrophin-1). IL-6 protein levels in serum and mouse myocardium were also significantly increased in response to ISO treatment. In cultured cardiac fibroblasts, IL-6 level was enhanced significantly after ISO (10^-6 mol/liter) stimulation for 2 h and then peaked at 12 h, whereas the response of IL-6 in cultured cardiomyocytes to ISO stimulation was not significant, suggesting that ISO-induced increase in IL-6 is primarily from cardiac fibroblasts rather than cardiomyocytes. Most importantly, IL-6 could activate STAT3 in a time-dependent manner in cultured cardiomyocytes, and inhibition of IL-6 level by anti-IL-6-neutralizing antibody clearly attenuated ISO-induced phosphorylation of STAT3 in myocardium. Taken together, these results indicate that -AR stimulation leads to a delayed STAT3 activation via an IL-6 family of cytokine-mediated pathway and that cardiac fibroblasts, but not cardiomyocytes, is probably the predominant source of IL-6 in response to ISO stimulation in mouse myocardium.

Received for publication, October 29, 2002 , and in revised form, March 3, 2003.

^* This work was supported in part by grants from the National Science Foundation of China (30070872) and by the Major State Basic Research Development Program of People's Republic of China (G2000056906). The costs of publication of this article were defrayed in part by the payment of page charges. This 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. Tel.: 86-10-62092306; Fax: 86-10-62017700; E-mail: zhangyy{at}bjmu.edu.cn.

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