PAK1 modulates a PPAR?/NF-?B cascade in intestinal inflammation.

ABSTRACT: P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling and its role in colitis-driven carcinogenesis. PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry, immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single intraperitoneal TNF? injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNF?. NF-?B and PPAR? were analyzed upon PAK1 overexpression and silencing for transcriptional/translational regulation. PAK1 expression and activation was increased on the luminal intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer. PAK1 was phosphorylated upon treatment with IFN?, IL-1?, and TNF?. In vivo, mice administered with TNF? showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-?B activation. p65 nuclear translocation downstream of TNF? was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1-p65 interaction as visualized by co-immunoprecipitation, nuclear translocation, and increased NF-?B transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPAR? and mesalamine recovered PPAR? through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-?B, which was recovered using BADGE, a PPAR? antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-?B activity via suppression of PPAR? in intestinal epithelial cells.

SUBMITTER: Dammann K 

PROVIDER: S-EPMC4576212 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature