We previously demonstrated that exposure of CCL39 lung fibroblasts to alpha -thrombin inhibits interleukin-6 (IL-6)-induced tyrosine phosphorylation of Stat3 (signal transducers and activators of transcription 3) via activation of mitogen-activated protein (MAP) kinase kinase 1 [Bhat et al. (1998) Arch. Biochem. Biophys. 350, 307-314]. In this study, using CCL39/MRC-5 cells, we investigated if additional signaling intermediates are involved in alpha -thrombin's inhibitory effects on IL-6-induced Stat3 signaling. We also determined if alpha -thrombin inhibits oncostatin M (OSM)-induced Stat3/Stat1, and interferon-gamma (IFN-gamma)-induced Stat1 tyrosine phosphorylation. We demonstrate that, although both IL-6 and OSM belong to the same cytokine family, alpha -thrombin inhibited only the IL-6-induced Stat3 tyrosine phosphorylation. The tyrosine phosphatase PTP1D coprecipitated with Stat3 from alpha -thrombin + IL-6, but not from alpha -thrombin + OSM-treated cells. Pretreatment of cells with a phosphatase inhibitor reversed the inhibitory actions of alpha -thrombin, suggesting a role for PTP1D in alpha -thrombin-mediated inhibition of IL-6-induced Stat3 signaling. Interestingly, alpha -thrombin failed to inhibit OSM- and IFN-gamma -induced Stat1 tyrosine phosphorylation. Cytokine-specific inhibition of the Stat3 signaling involving AM-P kinase kinase I and PTP1D by alpha -thrombin may play an important role in regulation of gene expression.