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INFLAMMATION/IMMUNITY/MEDIATORS

Regulation of RELM/FIZZ isoform expression by Cdx2 in response to innate and adaptive immune stimulation in the intestine

¹Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, ²Division of Gastroenterology, University of Pennsylvania School of Medicine, and ⁴Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania; and ³Division of Veterinary Clinical Studies, University of Edinburgh, Easter Bush Veterinary Centre, Roslin, Midlothian, United Kingdom

Submitted 29 September 2004 ; accepted in final form 24 November 2004

Host immune responses to commensal flora and enteric pathogens are known to influence gene expression in the intestinal epithelium. Although the Cdx family of caudal-related transcription factors represents critical regulators of gene expression in the intestinal epithelium, the effect of intestinal immune responses on Cdx expression and function has not been determined. We have shown that bacterial colonization and Th2 immune stimulation by intestinal nematode infection induce expression of the intestinal goblet cell-specific gene RELM. In this study, we investigated the transcriptional regulation of resistin-like molecule/found in inflammatory zone (RELM/FIZZ, RELM) and its isoforms RELM and RELM to ascertain the role of Cdx in modifying intestinal gene expression associated with innate and adaptive immune responses. Analysis of the RELM promoter showed that Cdx2 plays a critical role in basal gene activation in vitro. This was confirmed in vivo using transgenic mice, where ectopic gastric and hepatic expression of Cdx2 induces expression of RELM, but not RELM or RELM, exclusively in the stomach. Although there was no quantitative change in colonic Cdx2 mRNA expression, protein distribution, or phosphorylation of Cdx2, bacterial colonization induced expression of RELM, but not RELM or RELM. In contrast, parasitic nematode infections activated colonic expression of all three RELM isoforms without alteration in Cdx2 expression. These results demonstrated that Cdx2 participates in directing intestine-specific expression of RELM in the presence of commensal bacteria and that adaptive Th2 immune responses to intestinal nematode infections can activate intestinal goblet cell-specific gene expression independent of Cdx2.

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