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MBC in Press, published online ahead of print March 19, 2008
Mol. Biol. Cell 10.1091/mbc.E07-07-0720

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Submitted on July 28, 2007
Revised on February 12, 2008
Accepted on March 6, 2008

Thrombin Induces Fibroblast CCL2/JE Production and Release via Coupling of PAR1 to G{alpha}q and Cooperation between ERK1/2 and Rho Kinase Signalling Pathways

Xiaoling Deng,* Paul F. Mercer,* Chris J. Scotton,* Annette Gilchrist,{dagger} and Rachel C. Chambers*

*Centre for Respiratory Research, University College London, London WC1E 6JF, United Kingdom; {dagger}Caden Biosciences, Madison, WI 53711

Monitoring Editor: Mark Ginsberg

Uncontrolled activation of the coagulation cascade following tissue injury has been implicated in both inflammation and tissue fibrosis. Thrombin exerts pluripotent cellular effects via its high-affinity receptor, proteinase activated receptor-1 (PAR1) and signaling via G{alpha}i/o, G{alpha}q or G{alpha}12/13. Activation of PAR1 on fibroblasts, a key effector cell in fibrosis, results in the induction of several mediators, including the potent monocyte and fibrocyte chemoattractant CCL2. The aim of this study was to identify the G-protein and signaling pathway involved in PAR1-mediated CCL2 production and release. Using a novel PAR1 antagonist which blocks the interaction between PAR1 and G{alpha}q, we report for the first time that PAR1 coupling to G{alpha}q is essential for thrombin-induced CCL2 gene expression and protein release in murine lung fibroblasts. We further demonstrate that these effects are mediated via the cooperation between ERK1/2 and Rho kinase signaling pathways: a calcium-independent PKC, c-Raf and ERK1/2 pathway was found to mediate PAR1-induced CCL2 gene transcription; whereas PLC, calcium-dependent PKC and Rho kinase pathway influences CCL2 protein release. We propose that targeting the interaction between PAR1 and G{alpha}q mayallow us to selectively interfere with PAR1 proinflammatory and profibrotic signaling, while preserving the essential role of other PAR1-mediated cellular responses.

Address correspondence to: Rachel C. Chambers (r.chambers{at}ucl.ac.uk)






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