Abstract
Introduction: Cytokines are produced by various immunnocompetent cells, as well as cancer cells. Some studies have been demonstrated IL-6 and IL-10 play an important role in evading host immune surveillance in tumor microenvironment, but interactions of both cytokines has not been fully understood. Therefore, the aim of this study is to reveal two mechanisms by IL-6 in human colon carcinoma cells. One is the system of IL-10 regulation by IL-6 and IFN\#947;, another is the biological function of IL-6 after activation of STAT3 in colon carcinoma cells. Methods and Results: Firstly, we examined the effect of proinflammatory cytokines on IL-10 expression in human colon carcinoma cells (COLO205). COLO205 cells were stimulated with or without cytokines. Northern blotting and ELISA revealed TNF\#945;, IL-1\#946;, or IL-6 upregulated IL-10 mRNA and protein expression. Especially, IL-6 was a potent inducer of IL-10. IL-6 induced IL-10 production in a dose dependent manner by ELISA. IL-10 was enhanced after co-stimulation with IL-6 and either TNF\#945;, IL-1\#946; or IL-8. By contrast, IFN\#947; inhibited IL-6 induced production of IL-10. IFN\#947; downregulated IL-6 receptor \#945; mRNA expression by Northern blotting. These results indicated IFN\#947; could suppress signal transduction by IL-6. Nextly, we evaluated the biological role of IL-6 in COLO205 cells. IL-6 does-dependently significantly promoted cell proliferation after 60 hr incubation by WTS-1 assay. IL-6 significantly promoted chemoinvasion by using matrigel coated insert well system. NIH3T3 cell supernatants were added in a lower chamber as a chemoattratant. Western-Immunoprecipitation analysis identified IL-6 does-dependently activated phosphorylation of STAT3. Its maximum effect was observed in 20-30 min after the stimulation with 10-100 ng/ml concentration of IL-6. Conclusion: Induction of tumor-derived IL-10 by IL-6 could act on host immune cells, resulting in immune suppression through a TH1/TH2 cytokines balance in tumor microenvironment. Secreted IL-6 from various cells surrounding tumor tissues would contribute to colon cancer progression after activation of STAT3. IL-6 and IL-10 would be one of therapeutic molecular targets in future colon cancer treatment.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1154.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO