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Defective arachidonate release and PGE2 production in Gi&agr;2‐deficient intestinal and colonic subepithelial myofibroblasts

Background: Mice lacking the pertussis toxin‐sensitive G‐protein subunit Gi&agr;2 spontaneously develop colitis and colon cancer. In the gut, arachidonate‐derived prostaglandin E2 (PGE2) modulates intestinal immune responses and epithelial restitution and is derived largely from subepithelial myofibroblasts. Methods: We tested whether known decreases in arachidonate release in cells lacking Gi&agr;2 would result in decreased PGE2 production and tissue PGE2 levels. PGE2 levels were significantly decreased in the colon of Gi&agr;2−/− mice. Results: Gi&agr;2−/− myofibroblasts from the small intestine and colon both released ≈50% less arachidonate and 3‐ to 7‐fold less PGE2 and 6‐keto PGF1&agr; in response to adenosine triphosphate, thrombin, tumor necrosis factor‐&agr;, or lipopolysaccharide, in a partially cyclooxygenase (COX)‐2‐dependent manner. Decreased arachidonate release did not appear to be caused by a defect in cPLA2 translocation in the absence of Gi&agr;2. Basal myofibroblast COX‐1 and COX‐2 expression was downregulated in Gi&agr;2−/− cells. No differences in proliferation rates were found between serum‐starved or serum‐activated wild‐type (WT) and Gi&agr;2−/− myofibroblasts. Finally, treatment of Gi&agr;2−/− mice with the EP4‐specific PGE2 receptor agonist ONO‐AE1‐329 significantly decreased the severity of established colitis. Conclusions: These findings confirm a requirement for Gi&agr;2 in intestinal and colonic myofibroblast‐derived prostanoid production and confirm the importance of mucosal PGE2 in the suppression of colitis.