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Am J Physiol Gastrointest Liver Physiol 292: G1511-G1519, 2007. First published March 1, 2007; doi:10.1152/ajpgi.00307.2006
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INFLAMMATION/IMMUNITY/MEDIATORS

Decreased MAPK- and PGE2-dependent IL-11 production in Gi{alpha}2–/– colonic myofibroblasts

Brian Hoang, Alice Trinh, and Robert A. Edwards

Department of Pathology, University of California Irvine, Irvine, California

Submitted 11 July 2006 ; accepted in final form 26 February 2007

Mice deficient in the G-protein alpha subunit Gi{alpha}2 spontaneously develop colitis and colon cancer. IL-11 is a pleiotropic cytokine known to protect the intestinal epithelium from injury in animal models of colitis and is produced by subepithelial myofibroblasts in response to inflammatory mediators including TGF-beta, IL-1beta, and PGE2. Arachidonic acid release and subsequent PGE2 production is significantly decreased in the colonic mucosa of Gi{alpha}2–/– mice, and we hypothesized that this would affect mucosal IL-11 production. Mucosal levels of IL-11 were found to be significantly decreased in Gi{alpha}2–/– mice despite the presence of mild colitis. Primary cultures of Gi{alpha}2–/– intestinal and colonic myofibroblasts (IMF and CMF, respectively) produced less basal and TGF-beta or IL-1beta-stimulated IL-11 mRNA and protein than wild-type cells. Inhibitors of ERK or p38 MAPK activation dose dependently inhibited IMF and CMF IL-11 production in response to TGF-beta stimulation, whereas 16,16 dimethyl-PGE2 and prostanoid receptor subtype-selective agonists induced IL-11 production. Treatment of animals with the EP4-specific agonist ONO-AE1-329 resulted in enhanced mucosal levels of IL-11, and increased IL-11 production by ex vivo cultured CMF. Modulation of cAMP levels produced diverging results, with enhancement of TGF-beta-induced IL-11 release in IMF pretreated with 8-Br-cAMP and inhibition in cells treated either with pertussis toxin or the PKA inhibitor H-89. These data suggest a physiological role for prostaglandins, MAPK signaling, and cAMP signaling for the production of myofibroblast-derived IL-11 in the mouse intestinal mucosa.

Gi{alpha}2 knockout mice; myofibroblasts; interleukin-11; ONO-AE1-329; PGE2


Address for reprint requests and other correspondence: R. A. Edwards, Dept. of Pathology, D449 Med Sci I, Univ. of California Irvine, Irvine, CA 92697-4800 (e-mail: redwards{at}uci.edu)






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