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J. Biol. Chem., Vol. 283, Issue 12, 7401-7410, March 21, 2008

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Hepatocyte Growth Factor Suppresses Proinflammatory NFB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells^*

Rujun Gong¹, Abdalla Rifai, Yan Ge, Shan Chen^¶, and Lance D. Dworkin

From the Division of Kidney Disease and Hypertension, Department of Medicine, and the Department of Pathology, Brown University School of Medicine, Providence, Rhode Island, 02903 and the ^¶Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing 400038, China

Activation of NFB is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor (HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NFB activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3β suppresses NFB p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3β consensus motif and could be directly phosphorylated by GSK3β both in vivo and in vitro, signifying Ser-468 of RelA/p65 as a putative substrate for GSK3β. In addition, the C terminus of RelA/p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3β. Moreover, this domain was required for efficient phosphorylation of Ser-468 and was indispensable for the physical interaction between RelA/p65 and GSK3β. HGF substantially intercepted this interaction by inactivating GSK3β. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NFB-dependent genes. Diminished phosphorylation at Ser-468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NFB activation was consistently mimicked by a selective GSK3β inhibitor or GSK3β knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3β. Collectively, our findings suggest that HGF has a potent suppressive effect on NFB activation, which is mediated by GSK3β, an important signaling transducer controlling RelA/p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease.

Received for publication, December 20, 2007

^* This work was supported by the Young Investigator Research Award from the Rhode Island Foundation for Health and Lifespan Developmental Grant (to R. G.) and National Institutes of Health Grant RO1-DK52314 (to L. D. D.) and AT001465-01A2 (to A. R.). 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: Dept. of Medicine, Brown University School of Medicine, 593 Eddy St., Providence, RI 02903. Tel.: 401-444-0989; Fax: 401-444-6849; E-mail: Rujun_Gong{at}Brown.edu.

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