HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 7, 4200-4209, February 15, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/7/4200    most recent M708142200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chandrasekar, B. Articles by Valente, A. J. Search for Related Content PubMed PubMed Citation Articles by Chandrasekar, B. Articles by Valente, A. J. Social Bookmarking                      What's this?

Interleukin-18 Suppresses Adiponectin Expression in 3T3-L1 Adipocytes via a Novel Signal Transduction Pathway Involving ERK1/2-dependent NFATc4 Phosphorylation^*

Bysani Chandrasekar¹, Devang N. Patel, Srinivas Mummidi, Jae-woo Kim^¶, Robert A. Clark, and Anthony J. Valente

From the Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, Texas 78229-4404, the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229-3900, and the ^¶Department of Biochemistry and Molecular Biology, Medical Research Center for Chronic Metabolic Disease, Yonsei University College of Medicine, Seoul 120-752, Korea

An inverse correlation between the pro-inflammatory cytokine interleukin-18 and the anti-atherogenic adipokine adiponectin has been reported in the chronic pathological conditions obesity, insulin resistance, coronary artery disease, and metabolic syndrome. We investigated whether this relationship is coincidental or has a causal basis. Here we show that interleukin-18 (IL-18) suppresses adiponectin transcription, mRNA expression, and secretion by 3T3-L1 adipocytes. IL-18 suppresses adiponectin promoter-reporter activity, an effect reversed by deletion or mutation of the NFATc4 core DNA-binding site. IL-18 induces NFATc4 phosphorylation (Ser⁶⁷⁶), nuclear translocation, and in vivo DNA binding. IL-18 induces ERK1/2 phosphorylation and enzyme activity, and pretreatment with the MEK inhibitor U0126, ERK1/2 inhibitor PD98059, or small interference RNA targeted to ERK1/2 attenuates ERK1/2 activation and NFATc4 phosphorylation. Finally, inhibition of ERK1/2 or NFATc4 knockdown reverses IL-18-mediated adiponectin suppression. In contrast to its inhibitory effects on adiponectin expression, IL-18 potently stimulates PAI-1 secretion. These data demonstrate for the first time that IL-18 selectively suppresses adiponectin expression via ERK1/2-dependent NFATc4 activation and suggest that the inverse relationship observed between IL-18 and adiponectin in various chronic pathological conditions is causally related. Thus, targeting IL-18 expression may enhance adiponectin expression and mitigate disease progression.

Received for publication, October 1, 2007 , and in revised form, December 4, 2007.

^* This work was supported in part by the Research Service of the Department of Veterans Affairs. 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.

¹ To whom correspondence should be addressed: Medicine/Cardiology, The University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-4598; Fax: 210-567-6960; E-mail: chandraseka{at}uthscsa.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. Venkatachalam, B. Venkatesan, A. J. Valente, P. C. Melby, S. Nandish, J. E. B. Reusch, R. A. Clark, and B. Chandrasekar WISP1, a Pro-mitogenic, Pro-survival Factor, Mediates Tumor Necrosis Factor-{alpha} (TNF-{alpha})-stimulated Cardiac Fibroblast Proliferation but Inhibits TNF-{alpha}-induced Cardiomyocyte Death J. Biol. Chem., May 22, 2009; 284(21): 14414 - 14427. [Abstract] [Full Text] [PDF]

				M.-A. Cornier, D. Dabelea, T. L. Hernandez, R. C. Lindstrom, A. J. Steig, N. R. Stob, R. E. Van Pelt, H. Wang, and R. H. Eckel The Metabolic Syndrome Endocr. Rev., December 1, 2008; 29(7): 777 - 822. [Abstract] [Full Text] [PDF]

				K. Venkatachalam, S. Mummidi, D. M. Cortez, S. D. Prabhu, A. J. Valente, and B. Chandrasekar Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2078 - H2087. [Abstract] [Full Text] [PDF]