Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways

The production of interleukin-6 (IL-6) has been discovered in a variety of human tumors. Here we report the expression of IL-6, IL-6 receptor alpha (IL- 6Ralpha), and gp130 in human esophageal carcinoma tissues. We further demonstrate that IL- 6 protects an esophageal carcinoma cell line CE48T/VGH from apoptosis induced by staurosporine. IL-6 stimulation induced a rapid phosphorylation of gp130 and STAT3, and a dominant-negative STAT3 completely abolished the antiapoptotic effect. IL-6 also activated ERK 1/2 in CE48T/VGH cells. Inhibition of the ERK activation by PD98059 and transfection of a dominant-negative ERK2 completely blocked the protection of IL- 6 against apoptosis. Thus, both STAT and MAP kinase pathways are responsible for the IL-6-delivered survival signal in human esophageal carcinoma cells. In contrast, PI3-K inhibitors only partially attenuated the effect of IL-6, suggesting that PI3-K does not play a major role in the antiapoptotic signal of IL- 6 in our system. To investigate whether IL- 6 could induce the production of antiapoptotic molecules, proteins of the Bcl-2 family were measured. While Bcl-2, Bcl- x(L),, and Bax were not affected, Mcl-1 was induced by IL-6 in human esophageal carcinoma cells. Our results suggest that IL- 6 may contribute to the progression of esophageal cancers in an autocrine or paracrine manner.