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J. Biol. Chem., Vol. 279, Issue 34, 35210-35218, August 20, 2004

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STAT Signaling Underlies Difference between Flagellin-induced and Tumor Necrosis Factor--induced Epithelial Gene Expression^*

Yimin Yu, Hui Zeng, Matam Vijay-Kumar, Andrew S. Neish, Didier Merlin¶, Shanthi V. Sitaraman, and Andrew T. Gewirtz¶||**

From the Departments of Pathology and Laboratory Medicine, Division of Digestive Diseases, Department of Medicine, and ^||Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30322

Both bacterial flagellin and the cytokine tumor necrosis factor- (TNF) are potent activators of intestinal epithelial cell pro-inflammatory gene expression in general; nonetheless, there seem to be distinct differences in the specific patterns of gene expression induced by these agonists. The goal of this study was to define one such difference and elucidate the signaling mechanism responsible for such differential gene induction by these agonists. We observed that expression of inducible nitric-oxide synthase is substantially induced by flagellin but only minimally expressed in response to TNF. This difference seemed to be underlain by differential induction of signal transducers and activators of transcription (STAT) activation in that, whereas flagellin and TNF seemed to be equipotent activators of p38 mitogen-activated protein kinase and nuclear factor-B, flagellin induced substantially higher levels of STAT-1 and -3 tyrosine phosphorylation. Such flagellin-induced STAT activation exhibited delayed kinetics and was ablated by treatment with cycloheximide. Flagellin-induced activation of STAT-3 was abolished via neutralizing antibodies to interleukin (IL)-6, but not interferon (IFN) nor IFN; none of these neutralizing antibodies had any effect on flagellin-induced STAT-1 tyrosine phosphorylation. Flagellin induced substantially more IL-6 expression than did TNF, but neither agonist elicited detectable levels of IFN expression. Flagellin-induced expression of inducible nitric-oxide synthase but not IL-6, was abolished by blocking STAT activation with AG490, and was reduced by blocking STAT-3 activation with anti-IL-6. Together, these results indicate that epithelial cell induction of flagellin-specific gene expression is mediated, in part, by STAT activation that results from autocrine activation via IL-6.

Received for publication, April 12, 2004 , and in revised form, June 4, 2004.

^* This work was supported by National Institutes of Health Center Grant R24-DK064399 and R01 Grants DK061417 (to A. T. G.), DK061941 (to D. M.), and DK002802 (to S. V. S.). 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 Crohn's and Colitis Foundation of America.

^** To whom correspondence should be addressed: Pathology-WRB 105H, 615 Michael St., Emory University, Atlanta GA 30322. Tel.: 404-712-9885; Fax: 404-727-8538; E-mail-agewirt{at}emory.edu.

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