C-X-C and C-C chemokine expression and secretion by the human colonic epithelial cell line, HT-29: differential effect of T lymphocyte-derived cytokines

Abstract

Differential chemokine production by colonic epithelial cells is thought to contribute to the characteristic increased infiltration of selected population of leukocytes cells in inflammatory bowel disease. We have previously demonstrated that IL-13 enhances IL-1alpha-induced IL-8 secretion by the colonic epithelial cell line HT-29. We have now explored the C-C chemokine expression and modulation in this system. The combination of TNF-alpha and IFN-gamma was the minimal stimulation required for regulated on activation, normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein (MCP-1) mRNA expression and secretion by HT-29 cells. The same stimulation induced a stronger IL-8 mRNA expression and secretion. Pretreatment with IL-13 or IL-4, reduced significantly the RANTES, and MCP-1, but not IL-8 mRNA expression and secretion. In contrast, IL-10 had no effect on either MCP-1, or RANTES, or IL-8 generation. Pretreatment of HT-29 cells with wortmannin suggested that the IL-13-induced inhibition of C-C chemokine expression is via activation of a wortmannin-sensitive phosphatidylinositol 3-kinase. These data demonstrate that colonic epithelial cell chemokine production can be differentially regulated by T cell-derived cytokines and suggest an interplay between epithelial cells and T lymphocytes potentially important in the intestinal inflammation.

Mice with a Selective Deletion of the CC Chemokine Receptors 5 or 2 Are Protected from Dextran Sodium Sulfate-Mediated Colitis: Lack of CC Chemokine Receptor 5 Expression Results in a NK1.1+ Lymphocyte-Associated Th2-Type Immune Response in the Intestine

“…CCR5 binds the CC chemokines macrophage-inflammatory protein (MIP)-1␣, MIP-1␤, and RANTES (20), which are released from intestinal epithelial cells upon exposure to inflammatory mediators (21,22). Expression of both MIP-1␣ and RANTES is increased in the intestinal mucosa in IBD (23)(24)(25).…”

Differential Expression and Polarized Secretion of CXC and CC Chemokines by Human Intestinal Epithelial Cancer Cell Lines in Response to Clostridium difficile Toxin A

“…IFN-γ or TNF-α induces differential up-regulation of CXC and CC chemokine secretions in colonic epithelial cell lines (23,31). In this study, the stimulation with C. difficile toxin A did not up-regulate IFN-γ expression in HT-29 and Caco-2 intestinal epithelial cells.…”

Cytokine-induced Apoptosis in Epithelial HT-29 Cells Is Independent of Nitric Oxide Formation

“…granulocyte/macrophage-colony stimulating factor and granulocyte-colony stimulating factor) expression by activated monocytes/macrophages or endothelial cells (1,6). Another target of IL-13 is epithelial cells and we have recently demonstrated that IL-13 can modulate chemokine generation from the human colonic epithelial cell line HT-29 (7,8) and inhibit iNOS expression and NO generation in this system (9). Activation of the signaling enzyme phosphatidylinositol 3-kinase (PI 3-kinase) by IL-13 is important for mediating these effects (8,10).…”

“…Another target of IL-13 is epithelial cells and we have recently demonstrated that IL-13 can modulate chemokine generation from the human colonic epithelial cell line HT-29 (7,8) and inhibit iNOS expression and NO generation in this system (9). Activation of the signaling enzyme phosphatidylinositol 3-kinase (PI 3-kinase) by IL-13 is important for mediating these effects (8,10). PI 3-kinase and its major downstream effector, the serine/threonine kinase protein kinase B (PKB), have been shown to be key mediators of growth factor-induced cell survival and protection against c-Myc-induced cell death in fibroblasts (11)(12)(13).…”

“…Although markers of cytokine-stimulated apoptosis, such as DNA fragmentation and phosphatidylserine externalization, are detectable from 8 to 24 h, time course experiments have revealed that other functional responses continue unabated. For instance, identical cytokine treatment can also stimulate up-regulation of iNOS and chemokine mRNA up to 24 h post-stimulation (7,20) and these responses can be downregulated by pretreatment with IL-13 (7,8,10). So, cytokineinduced expression of apoptotic markers and events do not necessarily correlate with abrogated cell function, at least in the time frame studied here.…”