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Cellular responses to α-thrombin are mediated through a G-protein-coupled receptor that undergoes proteolytic cleavage, unveiling a tethered peptide ligand with the amino-terminal sequence SFLLRN. The synthetic peptide SFLLRN can mimic many of thrombin's actions via directly stimulating the thrombin receptor. Thrombin has been implicated in several cellular events associated with tissue injury, including fibroblast growth, matrix deposition, and inflammatory responses. The role of the thrombin receptor in fibroblast-dependent release of the inflammatory mediator prostaglandin E2was evaluated and compared to its well-characterized effect on cell proliferation. Both thrombin and SFLLRN stimulated [3H]thymidine incorporation into DNA but failed to induce prostaglandin E2release from CCL39 cells. The inflammatory cytokine interleukin-1β synergized with thrombin and SFLLRN to induce the release of prostaglandin E2, whereas it had no effect on thrombin receptor-mediated DNA synthesis. Interleukin-1β had no direct effects on thrombin receptor-mediated phosphoinositide hydrolysis, suggesting that its effects were downstream from early signal transduction events. Thrombin and interleukin-1β together significantly increased the expression of prostaglandin H synthase-2 in accordance with the prostaglandin E2results. These studies indicate that the fibroblast thrombin receptor differentially couples to intracellular signaling pathways leading to distinct functional responses and that thrombin receptor–effector interactions could be modulated by interleukin-1β.