Abstract
Colonic biopsies from inflamed colon have higher levels of epithelial apoptosis than biopsies from healthy individuals. Therapies that decrease intestinal epithelial apoptosis may decrease the inflammation observed in inflammatory bowel disease. We previously showed that signaling by PAR2, a GPCR activated by serine proteases, delayed IFN‐γ & TNF‐α‐induced apoptosis in colonic epithelial (HT‐29) cells. We aimed to determine the mechanism responsible for PAR2‐induced survival. The PAR2 agonists 2‐furoyl‐LIGRLO (2fLI), SLIGKV and trypsin all significantly reduced cleavage of caspase‐8, 9, 3 as well as PARP in response to IFNγ/TNFα. 2fLI increased phosphorylation of ERK1/2, p90RSK and Akt. 2fLI treatment stimulated the phosphorylation of pro‐apoptotic BAD at Ser112 and Ser136. Selective MAPK pathway inhibitors (U0126 & SL0101) blocked BAD Ser112 phosphorylation, whereas the PI3K‐selective inhibitor (LY294002) blocked BAD Ser136 phosphorylation. Pre‐treatment with 2fLI prior to the addition of IFNγ/TNFα increased BAD phosphorylation at both residues. PAR2 signaling reduces epithelial apoptosis in response to inflammatory cytokines via activation of pathways that inactivate the pro‐apoptotic BAD protein. Our findings may represent a mechanism whereby proteases facilitate epithelial cell survival and colonic healing after inflammation.Funding: Crohn's and Colitis Foundation of Canada
Published Version
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