期刊
MOLECULAR BIOLOGY OF THE CELL
卷 19, 期 6, 页码 2520-2533出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E07-07-0720
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资金
- British Lung Foundation [P03/8]
- Rosetrees Trust
- Wellcome Trust [GR071124MA]
- Medical Research Council UK
- Hutchinson Whampoa
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 (PAR(1)) 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 PAR(1)-mediated CCL2 production and release. Using a novel PAR1 antagonist that 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 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 alpha(q) may allow us to selectively interfere with PAR1 proinflammatory and profibrotic signaling, while preserving the essential role of other PAR1-mediated cellular responses.
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