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J. Biol. Chem., Vol. 281, Issue 27, 18560-18568, July 7, 2006

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Role of MyD88 in Phosphatidylinositol 3-Kinase Activation by Flagellin/Toll-like Receptor 5 Engagement in Colonic Epithelial Cells^*

Sang Hoon Rhee, Ho Kim, Mary P. Moyer, and Charalabos Pothoulakis¹

From the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 and INCELL Corporation, San Antonio, Texas 79249

Bacterial flagellin, recognized by Toll-like receptor (TLR) 5, is suggested to be involved in colonic inflammation. However, the detailed signaling mechanisms mediated by flagellin/TLR5 engagement are not clear. Here we dissected the biochemical mechanism by which TLR5 engagement mediates phosphatidylinositol 3-kinase (PI3K) activation in colonic epithelial cells. We demonstrate that silencing TLR5 expression in nontransformed human colonic epithelial cells blocks flagellin-induced PI3K activation, indicating specific activation of PI3K by flagellin/TLR5 engagement. Moreover, we determine that TLR5 recruits the p85 regulatory subunit of PI3K to its cytoplasmic TIR domain in response to flagellin. However, the Src homology binding "YXXM" motif in the cytoplasmic TIR domain of TLR5 is not involved in p85 recruitment, implying that TLR5 indirectly recruits p85. Indeed, we demonstrate that the adaptor molecule MyD88 associates with TLR5 and silencing MyD88 expression blocks PI3K activation by disrupting the association between TLR5 and p85. Furthermore, we show that MyD88 associates with p85 in response to flagellin. Additionally, we determine that blocking PI3K activation reduces interleukin-8 production induced by flagellin in human colonic epithelial cells. Together, MyD88 bridges TLR5 engagement to PI3K activation in response to flagellin.

Received for publication, December 29, 2005 , and in revised form, April 12, 2006.

^* This work was supported by a senior research award (to C. P.) and a research fellowship award (to S. H. R.) from the Crohn's and Colitis Foundation of America, Inc. 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: Beth Israel Deaconess Medical Center, Harvard Medical School, Gastrointestinal Neuropeptide Center, Division of Gastroenterology, Dana 601, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-1259; Fax: 617-667-2767; E-mail: cpothoul{at}bidmc.harvard.edu.

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