1. ¹Department of Pathology, The University of Chicago, Chicago, IL, USA
2. ²Department of Medicine, The Inflammatory Bowel Disease Research Center, The University of Chicago, Chicago, IL, USA

Correspondence: Dr J Sun, PhD, Department of Pathology, The University of Chicago, 5841 S Maryland Avenue, Chicago, IL 60637, USA. E-mail: jsun@bsd.uchicago.edu

Received 7 September 2006; Revised 24 January 2007; Accepted 25 January 2007; Published online 26 March 2007.

Abstract

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