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Decreased MAPK- and PGE2-dependent IL-11 production in Giα2–/– colonic myofibroblasts

Decreased MAPK- and PGE2-dependent IL-11 production in Giα2–/– colonic myofibroblasts Mice deficient in the G-protein alpha subunit G i α 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- , IL-1 , and PGE 2 . Arachidonic acid release and subsequent PGE 2 production is significantly decreased in the colonic mucosa of G i α 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 G i α 2 –/– mice despite the presence of mild colitis. Primary cultures of G i α 2 –/– intestinal and colonic myofibroblasts (IMF and CMF, respectively) produced less basal and TGF- or IL-1 -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- stimulation, whereas 16,16 dimethyl-PGE 2 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- -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. G i α 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@uci.edu ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Gastrointestinal and Liver Physiology The American Physiological Society

Decreased MAPK- and PGE2-dependent IL-11 production in Giα2–/– colonic myofibroblasts

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References (37)

Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0193-1857
eISSN
1522-1547
DOI
10.1152/ajpgi.00307.2006
pmid
17332478
Publisher site
See Article on Publisher Site

Abstract

Mice deficient in the G-protein alpha subunit G i α 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- , IL-1 , and PGE 2 . Arachidonic acid release and subsequent PGE 2 production is significantly decreased in the colonic mucosa of G i α 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 G i α 2 –/– mice despite the presence of mild colitis. Primary cultures of G i α 2 –/– intestinal and colonic myofibroblasts (IMF and CMF, respectively) produced less basal and TGF- or IL-1 -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- stimulation, whereas 16,16 dimethyl-PGE 2 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- -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. G i α 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@uci.edu )

Journal

AJP - Gastrointestinal and Liver Physiology – The American Physiological Society

Published: Jun 1, 2007

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