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J. Biol. Chem., Vol. 280, Issue 6, 4048-4057, February 11, 2005

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Interferon- Down-regulates Adenosine 2b Receptor-mediated Signaling and Short Circuit Current in the Intestinal Epithelia by Inhibiting the Expression of Adenylate Cyclase^*

Vasantha Kolachala, Vivian Asamoah, Lixin Wang, Shanthi Srinivasan, Didier Merlin, and Shanthi V. Sitaraman

From the Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322

Adenosine is an endogenous signaling molecule that is highly up-regulated in inflammatory states. Adenosine acts through the A2b receptor, a G protein-coupled receptor that couples positively to G_s and activates adenylate cyclase. This leads to cAMP-mediated electrogenic chloride secretion in intestinal epithelia. To better understand the regulation of the A2b receptor in intestinal epithelia, we studied the effects of interferon- (IFN-), a potent immunomodulatory cytokine, in the T84 cell line. Pretreatment of cells with 500 units/ml IFN- for 12 h inhibited an adenosine-induced short circuit current (I_sc) without affecting the transepithelial resistance. Under these conditions, IFN- did not inhibit the protein expression or membrane recruitment of the A2b receptor, shown to be essential for its function. Interestingly, IFN- inhibited cAMP levels as well as its downstream signaling pathway as shown by the inhibition of adenosine-induced phosphorylation of cAMP response element-binding protein and protein kinase A activity. Similar studies with forskolin, a direct activator of adenylate cyclase, also demonstrated inhibition of cAMP and its downstream response by IFN-. However, IFN- did not affect secretory responses to the calcium-dependent secretagogue carbachol or cAMP analog 8-bromo-cAMP, indicating that normal secretory responses to adequate second messengers in IFN--treated cells are achievable. Moreover, IFN- inhibited the expression of adenylate cyclase isoforms 5 and 7. In conclusion, we demonstrate that IFN- down-regulates adenosine-mediated signaling possibly through the direct inhibition of adenylate cyclase expression. We propose that IFN- may acutely affect global cAMP-mediated responses in the intestinal epithelia, thereby decreasing secretory responses, which may consequently aggravate inflammatory processes.

Received for publication, August 20, 2004 , and in revised form, November 5, 2004.

^* This work was supported by NIDDK, National Institutes of Health Grants DK 02802, DK 064644, and DK06411 (to S. V. S), DK 02831 (to D. M), and Digestive Disease Research Center Grant 5R24DK064399-02. 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: Division of Digestive Diseases, Emory University School of Medicine, Whitehead Research Bldg., Rm. 201-F, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-2430; Fax: 404-727-5767; E-mail: ssitar2{at}emory.edu.

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