Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells

Abstract

Human intestinal epithelial cells inducibly express neutrophil and monocyte chemoattractants, yet little is known about the regulated production of T-cell chemoattractants by the intestinal epithelium. IP-10, Mig, and I-TAC are 3 CXC chemokines that are known to act as CD4(+) T-cell chemoattractants. We studied constitutive chemokine expression in human colon, and defined the regulated expression of these chemokines by reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistology using cultured human intestinal epithelial cell lines and a novel adaptation of an in vivo human intestinal xenograft model. IP-10 and Mig were constitutively expressed by normal human colon epithelium, and their cognate receptor, CXCR3, was expressed by mucosal mononuclear cells. Interferon (IFN)-gamma stimulation increased mRNA expression and the polarized basolateral secretion of these chemokines by human colon epithelial cell lines; infection with enteroinvasive bacteria, or stimulation with the proinflammatory cytokines tumor necrosis factor alpha and interleukin 1alpha, strongly potentiated IFN-gamma-induced epithelial cell IP-10, Mig, and I-TAC production. Epithelial cell mRNA and protein expression of IP-10, Mig, and I-TAC were rapidly up-regulated in human intestinal xenografts in response to stimulation with IFN-gamma alone or in combination with IL-1. The constitutive and regulated production of the IFN-gamma-inducible chemokines IP-10, Mig, and I-TAC by human intestinal epithelium, and the expression of their cognate receptor, CXCR3, by mucosal mononuclear cells, suggest that the intestinal epithelium can play a role in modulating physiologic and pathologic T cell-mediated mucosal inflammation.