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J. Biol. Chem., Vol. 283, Issue 20, 14100-14108, May 16, 2008

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Differential Regulation of the IL-17 Receptor by c Cytokines

INHIBITORY SIGNALING BY THE PHOSPHATIDYLINOSITOL 3-KINASE PATHWAY^*

Matthew J. Lindemann, Zihua Hu, Marta Benczik, Kathleen D. Liu^¶, and Sarah L. Gaffen^||1

From the Department of Oral Biology, the ^||Department of Microbiology and Immunology, and the Department of Biostatistics and Center of Excellence in Bioinformatics, University at Buffalo, State University of New York, Buffalo, New York 14214 and the ^¶Department of Medicine, University of California at San Francisco, San Francisco, California 94143

The c-family cytokine IL-2 activates signaling events that contribute to cell survival and proliferation, the best-studied of which are the STAT-5 and phosphatidylinositol 3-kinase (PI3K) pathways. The starting point of this study was to define genes regulated by the IL-2R-mediated PI3K pathway in T cells. Accordingly, we used an erythropoietin (EPO) receptor chimeric receptor system in which IL-2-dependent HT-2 T cells expressed a mutant EPO-IL-2Rβ construct where Tyr-338 is mutated to Phe. Cells expressing this mutant IL-2Rβ chain fail to induce phosphorylation of PI3K-p85/β or activate Akt, but mediate normal IL-2-dependent proliferation and activation of JAK1 and STAT-5A/B. Microarray analyses revealed differential regulation of numerous genes compared with cells expressing a wild-type IL-2Rβ, including up-regulation of the IL-17 receptor subunit IL-17RA. Blockade of the PI3K pathway but not p70^S6K led to up-regulation of IL-17RA, and constitutive Akt activation was associated with suppressed IL-17RA expression. Moreover, similar to the mutant EPO-IL-2Rβ chimera, IL-15 and IL-21 induced IL-17RA preferentially compared with IL-2, and IL-2 but not IL-15 or IL-21 mediated prolonged activation of the PI3K p85 regulatory subunit. Thus, there are intrinsic signaling differences between IL-2 and IL-15 that can be attributed to differences in activation of the PI3K pathway.

Received for publication, February 20, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI05439 and AR050458 (to S. L. G.). This work was also supported by Training Grant DE007034 from the Department of Oral Biology at SUNY Buffalo (to M. J. L.). 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 Fig. S1 and Tables S1 and S2.

¹ To whom correspondence should be addressed: 36 Foster Hall, 3435 Main St., Buffalo NY 14214. Tel.: 716-829-2786; Fax: 716-829-3942; E-mail: sgaffen{at}buffalo.edu.