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  • Title: Inhibition of proinflammatory RANTES expression by TGF-beta1 is mediated by glycogen synthase kinase-3beta-dependent beta-catenin signaling.
    Author: Dai C, Wen X, He W, Liu Y.
    Journal: J Biol Chem; 2011 Mar 04; 286(9):7052-9. PubMed ID: 21189258.
    Abstract:
    TGF-β1 is a pleiotropic cytokine with potent anti-inflammation property. However, the mechanisms underlying TGF-β1 suppression of inflammation remain largely unexplored. In this study, we demonstrated that TGF-β1 inhibited TNF-α- or IL-1-induced RANTES expression in human kidney tubular epithelial cells (HKC-8). To delineate the mechanism by which TGF-β1 inhibits RANTES expression, we examined the potential signal pathway activated by TGF-β1 in suppressing NF-κB signaling. TGF-β1 affected neither TNF-α-induced IκBα phosphorylation and subsequent degradation, nor p65 NF-κB phosphorylation and its nuclear translocation. However, TGF-β1 could inhibit p65 and p50 binding to the κB site in human RANTES promoter as revealed by chromatin immunoprecipitation assay and protein-DNA binding assay. We found that TGF-β1 induced glycogen synthase kinase-3β (GSK-3β) phosphorylation on Ser-9 in HKC-8 cells, leading to its inactivation. Knockdown of GSK-3β mimicked TGF-β1 and inhibited RANTES induction, whereas overexpression of GSK-3β abolished the inhibitory effect of TGF-β1 and completely restored RANTES expression. Furthermore, TGF-β1 induced the dephosphorylation and activation of β-catenin, a major downstream target of GSK-3β. Ectopic expression of constitutively active β-catenin mimicked the TGF-β1 effect and completely suppressed RANTES expression induced by TNF-α. Interestingly, TGF-β1 induced a physical interaction between β-catenin and p65 NF-κB, which prevented p65 binding to the κB site, sequestered its trans-activating activity, and repressed p65-mediated gene transcription. We conclude that TGF-β1 inhibition of proinflammatory RANTES expression is mediated by β-catenin-triggered blockade of NF-κB signaling.
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