Beta‐catenin activity negatively regulates bacteria‐induced inflammation

Wild‐type (WT) Salmonella typhimurium cause acute intestinal inflammation by activating the NF‐kappaB pathway. Interestingly, WT Salmonella infection also causes degradation of beta‐catenin, the regulator of cell proliferation. Regulation of beta‐catenin and the inhibitor of NF‐kappa B, I kappa B alpha, are strikingly similar, involving phosphorylation at the same sites, ubiquitination by the same E3 ligase, and subsequent proteasomal degradation. However, how beta‐catenin directly regulates the NF‐kappa B pathway during bacteria‐induced inflammation in vivo is unknown. Using streptomycin‐pretreated mice challenged with Salmonella, we demonstrated that WT Salmonella stimulated beta‐catenin degradation and decreased the physical association between NF‐kappa B and beta‐catenin. Accordingly, WT Salmonella infection decreased the expression of c‐myc, a beta‐catenin‐regulated target gene and increased the levels of IL‐6 and TNF‐alpha, the NF kappa B‐regulated target genes. Bacterial infection directly stimulated phosphorylation of beta‐catenin, both in vivo and in vitro. Closer examination revealed that GSK‐3beta kinase activity was increased in response to WT Salmonella whereas non‐virulent Salmonella had no effect. Additionally, cells expressing constitutively active beta‐catenin showed I kappa B stabilization and inhibition of NF‐kappa B activity not only after WT Salmonella, but also after commensal bacteria (E. coli F18). This study indicates a new role for beta‐catenin as a negative regulator of inflammation.