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Vol. 19, Issue 6, 2520-2533, June 2008

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Thrombin Induces Fibroblast CCL2/JE Production and Release via Coupling of PAR₁ to G_q and Cooperation between ERK1/2 and Rho Kinase Signaling Pathways

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

*Centre for Respiratory Research, University College London, London WC1E 6JJ, United Kingdom; and Caden Biosciences, Madison, WI 53711

Submitted July 28, 2007; Revised February 12, 2008; Accepted March 6, 2008
Monitoring Editor: Mark Ginsberg

Uncontrolled activation of the coagulation cascade after 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_i/o, G_q, or G_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 that blocks the interaction between PAR₁ and G_q, we report for the first time that PAR₁ coupling to G_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 protein kinase C (PKC), c-Raf, and ERK1/2 pathway was found to mediate PAR₁-induced CCL2 gene transcription, whereas a phospholipase C, calcium-dependent PKC, and Rho kinase pathway influences CCL2 protein release. We propose that targeting the interaction between PAR₁ and G_q may allow 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).

Abbreviations used: ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; ca-MEK1, constitutively active MEK1; dn-MEK1, dominant negative-MEK1; EGFP, enhanced green fluorescent protein; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; KO, knockout; MLF, mouse lung fibroblast; PAR, proteinase-activated receptor; wt-MEK1, wild-type MEK1.

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