PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation

Kyle Dammann, Vineeta Khare, Michaela Lang, Thierry Claudel, Felix Harpain, Nicolas Granofszky, Rayko Evstatiev, Jonathan M. Williams, D. Mark Pritchard, Alastair Watson, Christoph Gasche

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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 TNFα injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFα. NF-κB and PPARγ 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 IFNγ, IL-1β, and TNFα. In vivo, mice administered with TNFα showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-κB activation. p65 nuclear translocation downstream of TNFα 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-κB transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPARγ and mesalamine recovered PPARγ through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-κB, which was recovered using BADGE, a PPARγ antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-κB activity via suppression of PPARγ in intestinal epithelial cells.
Original languageEnglish
Pages (from-to)2349–2360
Number of pages12
JournalBiochimica et Biophysica Acta (BBA) - Molecular Cell Research
Volume1853
Issue number10, Part A
Early online date31 May 2015
DOIs
Publication statusPublished - Oct 2015

Keywords

  • PAK1
  • NF-kB
  • PPARy
  • Inflammation
  • Ulcerative colitis
  • Colitis-associated cancer

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