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

Dammann, Kyle, Khare, Vineeta, Lang, Michaela, Claudel, Thierry, Harpain, Felix, Granofszky, Nicolas, Evstatiev, Rayko, Williams, Jonathan M., Pritchard, D. Mark, Watson, Alastair ORCID: https://orcid.org/0000-0003-3326-0426 and Gasche, Christoph (2015) PAK1 modulates a PPARγ/NF-κB cascade in intestinal inflammation. Biochimica Et Biophysica Acta-Molecular Cell Research, 1853 (10, Part A). 2349–2360. ISSN 0167-4889

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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.

Item Type:	Article
Additional Information:	Open Access funded by Austrian Science Fund (FWF) Under a Creative Commons license (CC BY-NC-ND)
Uncontrolled Keywords:	pak1,nf-kb,ppary,inflammation,ulcerative colitis,colitis-associated cancer,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User:	Pure Connector
Date Deposited:	24 Jul 2015 22:46
Last Modified:	25 Sep 2024 11:56
URI:	https://ueaeprints.uea.ac.uk/id/eprint/53688
DOI:	10.1016/j.bbamcr.2015.05.031

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