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Interferon gamma induces differential upregulation of alpha and beta chemokine secretion in colonic epithelial cell lines.

ABSTRACT: BACKGROUND: Production of chemoattractant factors by the intestinal epithelium may contribute to mucosal infiltration by inflammatory cells in inflammatory bowel disease. Secretion of the alpha chemokine interleukin 8 (IL-8), a neutrophil chemoattractant, has been widely studied, but little is known about epithelial secretion of beta chemokines, which are preferentially involved in recruiting monocytes. AIMS: To investigate the profiles of alpha and beta chemokine secretion in colonic cell lines and their differential modulation by interferon gamma (IFN-gamma), a product of activated T lymphocytes and natural killer cells. METHODS AND RESULTS: HT29-19A, a model of the CT secretory crypt cell, exhibited a parallel secretion of the alpha chemokines IL-8 and GRO alpha, which could be markedly upregulated by tumour necrosis factor alpha (TNF-alpha) and IL-1 beta. These cells showed no significant expression of the beta chemokines RANTES (regulated upon activation T cell expressed and secreted), MIP-1 alpha (macrophage inflammatory protein 1 alpha), and MCP-1 (monocyte chemotactic protein 1) under these conditions, but IFN-gamma in combination with TNF-alpha caused a dose dependent induction of RANTES and MCP-1 secretion. This was accompanied by a marked increase of RANTES mRNA. In contrast, IFN-gamma had no significant effect on TNF-alpha stimulated IL-8 secretion. Caco-2 cells, with features more typical of villus absorptive cells, were relatively poor secretors of alpha chemokines but secreted high levels of MCP-1 in response to IL-1 beta. IFN-gamma did not influence alpha or beta chemokine secretion in these cells. CONCLUSIONS: These studies suggest that intestinal epithelial cells may produce chemokines capable of attracting both neutrophils and monocytes. The ability of IFN-gamma to activate the expression of beta chemokines preferentially could facilitate the development of chronic inflammatory infiltrates.

SUBMITTER: Warhurst AC

PROVIDER: S-EPMC1726988 | biostudies-other | 1998 Feb

REPOSITORIES: biostudies-other

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Project description:Background & aimsMany colon cancers produce the hormone progastrin, which signals via autocrine and paracrine pathways to promote tumor growth. Transgenic mice that produce high circulating levels of progastrin (hGAS) have increased proliferation of colonic epithelial cells and are more susceptible to colon carcinogenesis than control mice. We investigated whether progastrin affects signaling between colonic epithelial and myofibroblast compartments to regulate tissue homeostasis and cancer susceptibility.MethodsColonic myofibroblast numbers were assessed in hGAS and C57BL/6 mice by immunohistochemistry. Human CCD18Co myofibroblasts were incubated with recombinant human progastrin (rhPG)(1-80) for 18 hours, and proliferation was assessed in the presence of pharmacologic inhibitors. The proliferation of human HT29 colonic epithelial cells was assessed after addition of conditioned media from CCD18Co cells incubated with progastrin. The effects of the insulin-like growth factor (IGF)-I receptor antagonist AG1024 were investigated in cultured HT29 cells and on the colonic epithelium of hGAS mice compared with mice that did not express transgenic progastrin (controls).ResultsThe colonic mucosa of hGAS mice contained greater numbers of myofibroblasts that expressed α-smooth muscle actin and vimentin than controls. Incubation of CCD18Co myofibroblasts with 0.1 nmol/L rhPG(1-80) increased their proliferation, which required activation of protein kinase C and phosphatidylinositol-3 kinase. CCD18Co cells secreted IGF-II in response to rhPG(1-80), and conditioned media from CCD18Co cells that had been incubated with rhPG(1-80) increased the proliferation of HT29 cells. The colonic epithelial phenotype of hGAS mice (crypt hyperplasia, increased proliferation, and altered proportions of goblet and enteroendocrine cells) was inhibited by AG1024.ConclusionsProgastrin stimulates colonic myofibroblasts to release IGF-II, which increases proliferation of colonic epithelial cells. Progastrin might therefore alter colonic epithelial cells via indirect mechanisms to promote neoplasia.

Project description:Cryptosporidium parvum is a protozoan parasite that infects intestinal epithelial cells and induces inflammation of the intestine. To better understand the inflammatory process occurring during cryptosporidiosis, we investigated in this study the kinetics of chemokine expression in the mucosa of mice by quantitative reverse transcription-PCR. Our results demonstrate that among the chemokine mRNAs studied, gamma interferon (IFN-gamma)-inducible protein 10 (IP-10), monokine induced by IFN-gamma (MIG), i-TAC, lymphotactin, macrophage inflammatory protein 1 beta (MIP-1 beta), and RANTES mRNAs were strongly up-regulated in infected neonate mice, which correlated with the immunofluorescence staining results showing T-cell and macrophage infiltration in the mucosa. Our in vitro data showed that intestinal epithelial cells infected by C. parvum or stimulated by the proinflammatory cytokines (IFN-gamma, interleukin-1 beta, and tumor necrosis factor alpha) produce a pattern of chemokine secretion similar to that observed in vivo, suggesting that these cells may take part in the initial production of chemokines. In order to identify the chemokines responsible for the recruitment of the inflammatory cells leading to a protective immune response, we compared the patterns of chemokine expression in a healing neonate mouse model and a nonhealing IFN-gamma knockout (GKO) mouse model of cryptosporidiosis. In the absence of IFN-gamma, the chemokine response was altered for IP-10, MIG, i-TAC, RANTES, and MIP-1 beta mRNAs, while the three ELR C-X-C chemokine mRNAs studied (lipopolysaccharide-induced C-X-C chemokine, MIP-2 alpha, and KC mRNAs) were strongly overexpressed. These results are consistent with the neutrophil recruitment observed in the lamina propria of GKO mice at day 9 postinfection but are not consistent with the hypothesis that these cells play an important role in the resolution of the infection. On the contrary, the altered response of chemokines responsible for the recruitment of macrophages and T cells in GKO mice suggests that these two populations may be critical in the development of a protective immune response.

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Interferon gamma induces differential upregulation of alpha and beta chemokine secretion in colonic epithelial cell lines.

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