alpha-thrombin inhibits interleukin-6-induced Stat3 signaling and gp130 gene expression in primary cultures of human lung fibroblasts

Exposure of primary human lung fibroblasts (HLF)to interleukin-6 (IL-6) rap idly induced Stat3 (signal transducers and activators of transcription 3) t yrosine phosphorylation. In these cells, alpha-thrombin did not induce tyro sine phosphorylation of Stat3; however, it potently induced its serine phos phorylation. Interestingly, a short pretreatment of cells with alpha-thromb in significantly inhibited IL-6-induced tyrosine phosphorylation of Stat3. The inhibition by alpha-thrombin was attenuated if cells were pretreated:wi th U0126, a specific inhibitor of the mitogen-activated protein (MAP) kinas e kinase 1 (MAPKK1). Exposure of HLF cells to IL-6 induced a twofold increa se in gp130 mRNA-levels; however, alpha-thrombin inhibited this IL-6-induce d-response almost to control levels. These results demonstrate, for the fir st time, that in HLF cells alpha-thrombin inhibits IL-6-induced Stat3 signa ling via activation of MAPKK1 and that this cross-talk regulates IL-6-induc ed gp130 gene expression. (C) 1999 Academic Press.