Journal Article

IL-6-induced survival of colorectal carcinoma cells is inhibited by butyrate through down-regulation of the IL-6 receptor

Hanna Yuan, Forrester J. Liddle, Sudipta Mahajan and David A. Frank

in Carcinogenesis

Volume 25, issue 11, pages 2247-2255
Published in print November 2004 | ISSN: 0143-3334
Published online November 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh246
IL-6-induced survival of colorectal carcinoma cells is inhibited by butyrate through down-regulation of the IL-6 receptor

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Colorectal carcinoma cells are characterized by over-expression of IL-6 and the IL-6 receptor, an autocrine loop that promotes the development of many tumors. To determine the importance of this pathway, we examined the role that IL-6 plays in the biology of 228 and RKO colorectal tumor cells. IL-6 induced prominent tyrosine phosphorylation of the transcription factor STAT1 in both cell types. Furthermore, IL-6 exerts functional effects in these cells in that it inhibited apoptosis induced by Fas ligation, and up-regulated Bcl-xl, a STAT target gene, which can promote cell survival. Butyrate, a compound formed in the intestines of people who consume a high-fiber diet, may confer protection against the development of colorectal cancer. Given the potential importance of IL-6 in the pathogenesis of colorectal tumors, we tested the hypothesis that butyrate acts by inhibiting IL-6-induced signaling events in colorectal carcinoma cells. Following treatment with butyrate, the activation of STAT1 in response to IL-6, but not interferon-γ, was completely lost. Butyrate induced a prominent decrease of mRNA and cell surface expression of the IL-6 receptor α (IL-6Rα) chain. Introduction of a soluble form of the IL-6Rα chain restored IL-6-induced STAT1 activation and resistance to apoptosis of butyrate treated cells. These experiments indicate that IL-6 may play an important role in the pathogenesis of colorectal cancers, and that butyrate may exert its protective effect by specifically blocking IL-6-induced signaling events.

Keywords: IL-6R, IL-6 receptor; IFN-γ, interferon-γ; PBS, phosphate-buffered saline; sIL-6Rα, soluble IL-6Rα chain

Journal Article.  6457 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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