Originally published In Press as doi:10.1074/jbc.M502586200 on May 11, 2005
J. Biol. Chem., Vol. 280, Issue 28, 26263-26277, July 15, 2005
The Pro-atherogenic Cytokine Interleukin-18 Induces CXCL16 Expression in Rat Aortic Smooth Muscle Cells via MyD88, Interleukin-1 Receptor-associated Kinase, Tumor Necrosis Factor Receptor-associated Factor 6, c-Src, Phosphatidylinositol 3-Kinase, Akt, c-Jun N-terminal Kinase, and Activator Protein-1 Signaling*
Bysani Chandrasekar
,
Srinivas Mummidi
,
Anthony J. Valente,
Devang N. Patel,
Steven R. Bailey¶,
Gregory L. Freeman,
Masahiko Hatano,
Takeshi Tokuhisa, and
Liselotte E. Jensen
From the
Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas 78229
We recently demonstrated that the chemokine CXCL16 is expressed in aortic smooth muscle cells (ASMC) and induces ASMC adhesion and proliferation (Chandrasekar, B., Bysani, S., and Mummidi, S. (2004) J. Biol. Chem. 279, 3188–3196). Here we reort that interleukin (IL)-18 positively regulates CXCL16 transcription in rat ASMC. We characterized the cis-regulatory region of CXCL16 and identified a functional activator protein-1 (AP-1) binding motif. Deletion or mutation of this site attenuated IL-18-mediated CXCL16 promoter activity. Gel shift, supershift, and chromatin immunoprecipitation assays confirmed AP-1-dependent CXCL16 expression. CXCL16 promoter-reporter activity was increased by constitutively active c-Fos and c-Jun and decreased by dominant negative or antisense c-Fos and c-Jun. Src kinase inhibitors PP1 and PP2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002, Akt inhibitor, the c-Jun N-terminal kinase (JNK) inhibitor SP600125, antisense JNK and dominant negative MyD88, interleukin-1 receptor-associated kinase (IRAK)-1, IRAK4, and phosphatidylinositol 3-kinase expression all attenuated IL-18-mediated AP-1 binding and reporter activity, CXCL16 promoter-reporter activity, and CXCL16 expression. Thus IL-18 induced CXCL16 expression via a MyD88 
IRAK1-IRAK4-TRAF6 (tumor necrosis factor receptor-associated factor 6) c-Src PI3K Akt JNK AP-1 pathway. Importantly, IL-18 stimulated ASMC proliferation in a CXCL16-dependent manner. These data provide for the first time a mechanism of IL-18-mediated CXCL16 gene transcription and CXCL16-dependent ASMC proliferation and suggest a role for IL-18-CXCL16 cross-talk in atherogenesis and restenosis following angioplasty.
Received for publication, March 8, 2005
, and in revised form, May 5, 2005.
* This work was supported in part by the NHLBI, National Institutes of Health Grant HL68020 and by a pilot grant from the Executive Research Committee at the University of Texas Health Science Center at San Antonio. It was presented in part at the 77th Scientific Sessions of the American Heart Association, New Orleans, LA, November 7–10, 2004. 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.
Supported by the Merit Review Entry Program of the Department of Veterans Affairs.
¶ Supported by the Janey Briscoe Center of Excellence in Cardiovascular Disease.
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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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
