We previously demonstrated that exposure of CCL39 lung fibroblast cells to alpha-thrombin inhibits interleukin-6 (IL-6)-induced tyrosine phosphorylation of Stat3 (signal transducers and activators of transcription-3) protein via a mitogen-activated protein (MAP)-kinase dependent mechanism. In the present study, we investigated the mechanism of regulation of IL-6-induced signaling by transforming growth factor-beta (TGF-beta) and compared this to alpha-thrombin-mediated inhibition. We demonstrate that exposure of CCL39 cells to TGF-beta completely inhibits IL-6-induced Stat3 tyrosine phosphorylation and gp130 gene expression. However, in contrast to alpha-thrombin, TGF-beta-mediated inhibition did not require activation of the MAP kinase pathway. Also, unlike alpha-thrombin, TGF-beta-mediated inhibition requires synthesis of new proteins. Interestingly, TGF-beta and alpha-thrombin both inhibit IL-6-induced expression of gp130 mRNA levels. These results demonstrate that although the end effects are the same, alpha-thrombin and TGF-beta utilize distinct mechanisms to inhibit IL-6-induced Stat3 signaling.
Copyright 2000 Academic Press.