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J. Biol. Chem., Vol. 283, Issue 21, 14213-14220, May 23, 2008

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Major Histocompatibility Class II Transactivator Expression in Smooth Muscle Cells from A2b Adenosine Receptor Knock-out Mice

CROSS-TALK BETWEEN THE ADENOSINE AND INTERFERON- SIGNALING^*

From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Atherosclerosis characterized by sustained inflammation and aberrant extracellular matrix alterations. Our previous investigation has defined major histocompatibility class II transactivator (CIITA) as a key factor in mediating these two processes in smooth muscle cells. Here, we demonstrate that CIITA and major histocompatibility class II expression are elevated in interferon- (IFN-)-treated smooth muscle cells from A2b adenosine receptor (A2bAR^–/–) knock-out mice, as compared with wild type cells. An A2-type adenosine receptor agonist suppresses these effects of IFN- in wild type cells, which can be blocked by an A2bAR-specific antagonist. We further identify that increased cellular cAMP levels are responsible for the down-regulation of CIITA expression and, hence, reduced IFN- response as evidenced by the following data: 1) direct activation of adenylyl cyclase activity is both necessary and sufficient to suppress the IFN- response; 2) inhibition of phosphodiesterase activity attenuates IFN- induced transcription events; and 3) direct treatment with cAMP analog abrogates CIITA activation and IFN- response. Therefore, our data establish possible cross-talk between the adenosine signaling through cAMP and IFN- during regulation of CIITA expression.

Received for publication, October 18, 2007 , and in revised form, March 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Public Health Services Grants HL68094 (to B. D. S.) and HL013262-31 (to B. D. S. and K. R.). This work was also supported by American Heart Association Post-doctoral Fellowship Grant 0525981T (to Y. X.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Established Investigator with the American Heart Association.

² To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4159; Fax: 617-638-5339; E-mail: smith{at}biochem.bumc.bu.edu.

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