Submitted on July 11, 2006
Accepted on February 26, 2007
Decreased MAPK- and PGE2-stimulated IL-11 production in Gi
2-/- small intestinal and colonic myofibroblasts
Brian Hoang1, Alice Tu Trinh1, and Robert A Edwards2*
1 Pathology, UC Irvine, Irvine, California, United States
2 Pathology & Lab Medicine, UC Irvine, Irvine, California, United States
* To whom correspondence should be addressed. E-mail: redwards{at}uci.edu.
Abstract: Mice deficient in the G-protein alpha subunit Gi
2 spontaneously develop colitis and colon cancer. Interleukin-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 PGE2. Arachidonic acid release and subsequent PGE2 production is significantly decreased in the colonic mucosa of Gi2-/- mice, and we hypothesized that this would affect mucosal IL-11 production. Mucosal levels of IL-11 were found to be significantly decreased in Gi2-/- mice despite the presence of mild colitis. Primary cultures of Gi2-/- intestinal and colonic myofibroblasts (IMF and CMF) produced less basal and TGF or IL-1-stimulated IL-11 mRNA and protein than WT cells. Inhibitors of ERK or p38 MAPK activation dose-dependently inhibited IMF/CMF IL-11 production in response to TGF stimulation, while 16,16 dimethyl-PGE2 and EP-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 physiologic role for prostaglandins, MAPK signaling, and cAMP signaling for the production of myofibroblast-derived IL-11 in the mouse intestinal mucosa.
