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The ability of Salmonella typhimuriu,n to enter intestinal epithelial cells constitutes a crucial step in pathogenesis. Salmonella invasion of the intestinal epithelium requires bacterial type three secretion system. Type three secretion system is a transport device that injects virulence proteins, called effectors, to paralyze or reprogram the eukaryotic cells. Avirulence factor for Salmonella (AvrA) is a Salmonella effector that inhibits the host's inflammatory responses. The mechanism by which AvrA modulates host cell signaling is not entirely clear. p53 is situated at the crossroads of a network of signaling pathways that are essential for genotoxic and nongenotoxic stress responses. We hypothesized that Salmonella infection activates the p53 pathway. We demonstrated that Salmonella infection increased p53 acetylation. Cells infected with AvrA-sufficient Salmonella have increased p53 acetylation, whereas cells infected with AvrA-deficient Salmonella have less p53 acetylation. In a cell-free system, AvrA possessed acetyltransferase activity and used p53 as a substrate. AvrA expression increased p53 transcriptional activity and induced cell cycle arrest. HCT116 p53-/- cells had less inflammatory responses. In a mouse model of Salmnonella infection, intestinal epithelial p53 acetylation was increased by AvrA expression. Our studies provide novel mechanistic evidence that Sal,nonella modulates the p53 pathway during intestinal inflammation and infection. [ABSTRACT FROM AUTHOR]

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, 1 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. [ABSTRACT FROM AUTHOR]