Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

• Published in: The Journal of biological chemistry Vol. 283; no. 12; p. 7401
• Main Authors: Rujun Gong, Abdalla Rifai, Yan Ge, Shan Chen, Lance D. Dworkin
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 21.03.2008
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M710396200

Activation of NFκB 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 NFκB activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3β suppresses NFκB 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 NFκB-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 NFκB 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 NFκB 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.