β-Catenin activity negatively regulates bacteria-induced inflammation

Abstract

Wild-type (WT) Salmonella typhimurium causes acute intestinal inflammation by activating the nuclear factor kappa B (NF-kB) pathway. Interestingly, WT Salmonella infection also causes degradation of b-catenin, a regulator of cellular proliferation. Regulation of b-catenin and the inhibitor of NF-kB, IkBa, is strikingly similar, involving phosphorylation at identical sites, ubiquitination by the same E3 ligase, and subsequent proteasomal degradation. However, how b-catenin directly regulates the NF-kB pathway during bacteria-induced inflammation in vivo is unknown. Using streptomycinpretreated mice challenged with Salmonella, we demonstrated that WT Salmonella stimulated b-catenin degradation and decreased the physical association between NF-kB and b-catenin. Accordingly, WT Salmonella infection decreased the expression of c-myc, a b-catenin-regulated target gene, and increased the levels of IL-6 and TNF-a, the NF-kB-regulated target genes. Bacterial infection directly stimulated phosphorylation of b-catenin, both in vivo and in vitro. Closer examination revealed that glycogen synthase kinase 3b (GSK-3b) kinase activity was increased in response to WT Salmonella, whereas non-virulent Salmonella had no effect. siRNA of GSK-3b was able to stabilize IkBa in response to WT Salmonella. Pretreatment for 24 h with LiCl, an inhibitor of GSK-3b, reduced WT Salmonella induced IL-8 secretion. Additionally, cells expressing constitutively active b-catenin showed IkBa stabilization and inhibition of NF-kB activity not only after WT Salmonella infection but also after commensal bacteria (Escherichia coli F18) and TNF-a treatment. This study suggests a new role for b-catenin as a negative regulator of inflammation. Bacteria pathogenicity requires overcoming or altering many very effective host defense mechanisms, 1 including the activation of nuclear factor kappa B (NF-kB). 2-4 Bacterial invasion of intestinal epithelial cells (IECs) stimulates NF-kB and, interestingly, degradation of b-catenin, 5 a potent transcriptional factor responsible for cellular proliferation and differentiation. It is notable that regulation of b-catenin and the inhibitor of NF-kB, IkBa, are strikingly similar, involving phosphorylation of the same N-terminal serine sequence sites, ubiquitination by the same E3 ligase complex, and subsequent proteasomal degradation. 6,7 To date, no publications have reported on the physiological significance of b-catenin's potential inter-relationship with the NF-kB inflammatory pathway after bacterial infection in vivo.In this study, therefore, we investigated the role of b-catenin in modulating the proinflammatory response mediated by NF-kB subsequent to Salmonella infection in vivo. We examined the possibility that b-catenin functions as a negative regulator of NF-kB, much in the same way as IkBa, through physical interaction with NF-kB. Additionally, we established the role of glycogen synthase kinase 3b (GSK-3b), as the negative regulator of b-catenin's stability and subsequent reactivity with NF-kB in both in vit...

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

“…Furthermore, XAV939 treatment or siRNA-mediated inhibition of β-catenin in infection led to an increase in NF-κB transcription and pro-inflammatory gene expression supporting a similar observation in other cell types. 21,34 Inhibition of β-catenin also resulted in increased host cell apoptosis with an overall decrease in parasite burden indicating its role downstream of AKT.…”

“…20 β-catenin limits NF-κB mediated inflammatory responses in both Salmonella infection and TNF-α treatment by stabilizing Iκβ. 21 We, therefore, were interested to determine whether these two downstream effector molecules of AKT are modulated by infection. The present paper demonstrates a mechanistic insight into how by exploiting a single host protein AKT, Leishmania inhibits both proinflammatory response and host cell apoptosis by activating β-catenin through inhibition of GSK-3β on one hand and inactivating FOXO-1 on the other hand.…”

Critical Roles of Notch and Wnt/β-Catenin Pathways in the Regulation of Hyperplasia and/or Colitis in Response to Bacterial Infection

“…Our study provides circumstantial evidence that in addition to the Wnt/␤-catenin pathway, Notch signaling is also activated during TMCH and may work in tandem with the Wnt/␤-catenin pathway to regulate hyperplasia and/or colitis following C. rodentium infection. We (23,24,28) and others (7,14) have shown that activation of the Wnt/␤-catenin pathway in the gut in response to bacterial infection is not unprecedented. However, neither the mechanism nor the consequence of aberrant regulation of the Notch pathway, either alone or in conjunction with Wnt/␤-catenin signaling, is clearly understood.…”

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

“…[181]. Another group of studies have shown that -catenin reduces Salmonella-induced inflammation in epithelial cells through an NFB-dependent mechanism [178] or a mechanism involving inhibition of GSK3mediated degradation [182]. On the other hand, -catenin is also associated with increased inflammatory cytokine production in various cell types.…”

“…In another study, LiCl treatment, which inhibits GSK3 activity and leads to β-catenin accumulation, resulted in reduction of Salmonella-induced IL-8 production. Moreover, cells expressing constitutively active -catenin had reduced NFB activity upon Salmonella infection [182].…”