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J. Biol. Chem., Vol. 282, Issue 37, 27229-27238, September 14, 2007

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Interleukin-17 Stimulates C-reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-dependent NF-B and C/EBP Activation^*

Devang N. Patel, Carter A. King, Steven R. Bailey, Jeffrey W. Holt, Kaliyamurthi Venkatachalam, Alok Agrawal, Anthony J. Valente, and Bysani Chandrasekar^¶1

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 Pharmacology, East Tennessee State University, Johnson City, Tennessee 37614

Elevated systemic levels of the acute phase C-reactive protein (CRP) are predictors of future cardiovascular events. There is evidence that CRP may also play a direct role in atherogenesis. Here we determined whether the proinflammatory interleukin (IL)-17 stimulates CRP expression in hepatocytes (Hep3B cell line and primary hepatocytes) and coronary artery smooth muscle cells (CASMC). Our results demonstrate that IL-17 potently induces CRP expression in Hep3B cells independent of IL-1 and IL-6. IL-17 induced CRP promoter-driven reporter gene activity that could be attenuated by dominant negative IB or C/EBP knockdown and stimulated both NF-B and C/EBP DNA binding and reporter gene activities. Targeting NF-B and C/EBP activation by pharmacological inhibitors, small interfering RNA interference and adenoviral transduction of dominant negative expression vectors blocked IL-17-mediated CRP induction. Overexpression of wild type p50, p65, and C/EBP stimulated CRP transcription. IL-17 stimulated p38 MAPK and ERK1/2 activation, and SB203580 and PD98059 blunted IL-17-mediated NF-B and C/EBP activation and CRP transcription. These results, confirmed in primary human hepatocytes and CASMC, demonstrate for the first time that IL-17 is a potent inducer of CRP expression via p38 MAPK and ERK1/2-dependent NF-B and C/EBP activation and suggest that IL-17 may mediate chronic inflammation, atherosclerosis, and thrombosis.

Received for publication, April 17, 2007 , and in revised form, July 9, 2007.

^* This work was supported in part by the Research Service of the Department of Veterans Affairs and NHLBI Grant HL68020 from the National Institutes of Health (to B. C.). 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.

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