beta-Catenin activity negatively regulates bacteria-induced inflammation.
Wild-type (WT) Salmonella typhimurium causes acute intestinal inflammation by activating the nuclear factor kappa B (NF-kappaB) pathway. Interestingly, WT Salmonella infection also causes degradation of beta-catenin, a regulator of cellular proliferation. Regulation of beta-catenin and the inhibitor of NF-kappaB, IkappaBalpha, is strikingly similar, involving phosphorylation at identical sites, ubiquitination by the same E3 ligase, and subsequent proteasomal degradation. However, how beta-catenin directly regulates the NF-kappaB 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-kappaB 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-kappaB-regulated target genes. Bacterial infection directly stimulated phosphorylation of beta-catenin, both in vivo and in vitro. Closer examination revealed that glycogen synthase kinase 3beta (GSK-3beta) kinase activity was increased in response to WT Salmonella, whereas non-virulent Salmonella had no effect. siRNA of GSK-3beta was able to stabilize IkappaBalpha in response to WT Salmonella. Pretreatment for 24 h with LiCl, an inhibitor of GSK-3beta, reduced WT Salmonella induced IL-8 secretion. Additionally, cells expressing constitutively active beta-catenin showed IkappaBalpha stabilization and inhibition of NF-kappaB activity not only after WT Salmonella infection but also after commensal bacteria (Escherichia coli F18) and TNF-alpha treatment. This study suggests a new role for beta-catenin as a negative regulator of inflammation.
Duan
Yingli
Y
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
Liao
Anne P
AP
Kuppireddi
Sumalatha
S
Ye
Zhongde
Z
Ciancio
Mae J
MJ
Sun
Jun
J
D000818:Animals; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012480:Salmonella Infections / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D015850:Interleukin-6; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D051550:I-kappa B Kinase; D038362:Glycogen Synthase Kinase 3