Alpha-Thrombin and interleukin-6 (IL-6) play important roles in inflammation, tissue repair and wound healing. Their cellular responses are mediated via activation of signal transduction pathways. While alpha- thrombin mediates its effects through numerous signaling intermediates including mitogen-activated protein (MAP) kinases, IL-6 acts via stimulation of the JAK-STAT (Janus kinase-Signal Transducers and Activators of Transcription) pathway. In primary human lung fibroblast cultures and established cell lines, we recently demonstrated that alpha- thrombin, through a MAP kinase 1-dependent mechanism, inhibits IL-6 induced tyrosine phosphorylation of Stat3 protein. Stat3 is a member of STAT family of transcription factors, and its activation by tyrosine phosphorylation is a critical event in IL-6 induced signaling. Alpha- Thrombin's capacity to inhibit IL-6-induced signaling defines a new role for this multi-functional serine protease. Transforming growth factor-beta also inhibits IL-6 induced signaling in lung fibroblast indicating that crosstalk also involves other agonists implicated in the pathogenesis of lung injury and repair. Our working hypothesis is that alpha-thrombin interferes with IL-6- induced signaling at multiple steps, mediated by the actions kinases/phosphatases. In this study, utilizing biochemical and molecular approaches, we will elucidate the mechanism by which alpha-thrombin inhibits IL-6-induced JAK-STAT signaling in lung fibroblasts, and identify IL-6 induced genes inhibited by alpha-thrombin via this crosstalk. This proposal will enhance our understanding of signaling mechanisms by which alpha-thrombin and IL-6 are locally expressed in the alveolar space during lung injury, elucidation of this regulatory pathway could suggest novel strategies to prevent or attenuate pulmonary inflammation and/or fibrosis.
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