Submitted on April 12, 2004
Accepted on June 30, 2004
Regulated production of the chemokine CCL28 in human colon epithelium
Hiroyuki Ogawa1, Mitsutoshi Iimura1, Lars Eckmann2, and Martin F. Kagnoff3*
1 Department of Medicine, University of California, La Jolla, CA, USA; Laboratory of Mucosal Immunology, University of Califnornia, La Jolla, CA, USA
2 Department of Medicine, University of California, La Jolla, CA, USA
3 Department of Medicine, University of California, La Jolla, CA, USA; Department of Pediatrics, University of California, La Jolla, CA, USA; Laboratory of Mucosal Immunology, University of Califnornia, La Jolla, CA, USA
* To whom correspondence should be addressed. E-mail: mkagnoff{at}ucsd.edu.
The chemokine CCL28 is constitutively expressed by epithelial cells at several mucosal sites, and is thought to function as a homeostatic chemoattractant of subpopulations of T cells and IgA B cells, and to mediate antimicrobial activity. We report herein on the regulation of CCL28 in human colon epithelium by the proinflammatory cytokine IL-1, bacterial flagellin and n-butyrate, a product of microbial metabolism. In vivo, CCL28 was markedly increased in the epithelium of pathologically inflamed compared to normal human colon. Human colon and small intestinal xenografts were used to model human intestinal epithelium in vivo. Xenografts constitutively expressed little, if any, CCL28 mRNA or protein. After stimulation with the proinflammatory cytokine IL-1, CCL28 mRNA and protein were significantly increased in the epithelium of colon but not small intestinal xenografts, although both upregulated the expression of another prototypic chemokine, CXCL8, in response to the identical stimulus. In studies of CCL28 regulation using human colon epithelial cell lines, proinflammatory stimuli, including IL-1, bacterial flagellin, and bacterial infection, significantly upregulated CCL28 mRNA expression and protein production. In addition, CCL28 mRNA expression and protein secretion by those cells were significantly increased by the short chain fatty acid n-butyrate, and IL-1- or flagellin-stimulated upregulation of CCL28 by colon epithelial cells was synergistically increased by pretreatment of cells with n-butyrate. Consistent with its upregulated expression by proinflammatory stimuli, CCL28 mRNA expression was attenuated by pharmacologic inhibitors of NF-
B activation. These findings indicate that CCL28 functions as an "inflammatory" chemokine in human colon epithelium and suggest the notion that CCL28 may act to counter-regulate colonic inflammation.
