β-Catenin activity negatively regulates bacteria-induced inflammation

Wild-type (WT) Salmonella typhimurium causes acute intestinal inflammation by activating the nuclear factor kappa B (NF-κB) pathway. Interestingly, WT Salmonella infection also causes degradation of β-catenin, a regulator of cellular proliferation. Regulation of β-catenin and the inhibitor of NF-κB, IκBα, is strikingly similar, involving phosphorylation at identical sites, ubiquitination by the same E3 ligase, and subsequent proteasomal degradation. However, how β-catenin directly regulates the NF-κB pathway during bacteria-induced inflammation in vivo is unknown. Using streptomycin-pretreated mice challenged with Salmonella, we demonstrated that WT Salmonella stimulated β-catenin degradation and decreased the physical association between NF-κB and β-catenin. Accordingly, WT Salmonella infection decreased the expression of c-myc, a β-catenin-regulated target gene, and increased the levels of IL-6 and TNF-α, the NF-κB-regulated target genes. Bacterial infection directly stimulated phosphorylation of β-catenin, both in vivo and in vitro. Closer examination revealed that glycogen synthase kinase 3β (GSK-3β) kinase activity was increased in response to WT Salmonella, whereas non-virulent Salmonella had no effect. siRNA of GSK-3β was able to stabilize IκBα in response to WT Salmonella. Pretreatment for 24 h with LiCl, an inhibitor of GSK-3β, reduced WT Salmonella induced IL-8 secretion. Additionally, cells expressing constitutively active β-catenin showed IκBα stabilization and inhibition of NF-κB activity not only after WT Salmonella infection but also after commensal bacteria (Escherichia coli F18) and TNF-α treatment. This study suggests a new role for β-catenin as a negative regulator of inflammation.