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J. Biol. Chem., Vol. 275, Issue 45, 35584-35591, November 10, 2000
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From the Centre for Cardiopulmonary Biochemistry and Respiratory
Medicine, Royal Free and University College Medical School, UCL, Rayne
Institute, 5 University Street, London WC1E 6JJ, United Kingdom
The coagulation protease thrombin plays a
critical role in hemostasis and exerts pro-inflammatory and
pro-fibrotic effects via proteolytic activation of the major thrombin
receptor, protease-activated receptor-1 (PAR-1). Connective tissue
growth factor (CTGF) is a novel fibroblast mitogen and also promotes
extracellular matrix protein production. It is selectively induced by
transforming growth factor
Thrombin Is a Potent Inducer of Connective Tissue Growth Factor
Production via Proteolytic Activation of Protease-activated
Receptor-1*
,
(TGF-) and is thought to be the
autocrine agent responsible for mediating its pro-fibrotic effects.
CTGF is up-regulated during tissue repair and in fibrotic conditions
associated with activation of the coagulation cascade. We therefore
hypothesized that coagulation proteases promote the production of
CTGF by cells at sites of tissue injury. To begin to address this
hypothesis, we assessed the effect of coagulation proteases on
fibroblast CTGF expression in vitro, and we show that
thrombin, at physiological concentrations, up-regulated CTGF mRNA
levels 5-fold relative to base line (p < 0.01) in
fetal fibroblasts and 7-fold in primary adult fibroblasts
(p < 0.01). These effects were
cycloheximide-insensitive and were not blocked with a pan-specific
TGF--neutralizing antibody. They were further paralleled by a
concomitant increase in CTGF protein production and could be mimicked
with selective PAR-1 agonists. In addition, fibroblasts derived from
PAR-1 knockout mice were unresponsive to thrombin but responded
normally to TGF-1. Finally, factor Xa, which is
responsible for activating prothrombin during blood coagulation,
exerted similar stimulatory effects. We propose that coagulation
proteases and PAR-1 may play a role in promoting connective tissue
formation during normal tissue repair and the development of fibrosis
by up-regulating fibroblast CTGF expression.
*
This work was supported by The Wellcome Trust Program Grant
051154, the British Lung Foundation Grant F93/12, and Johnson & Johnson
Medical UK.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Tel.: 44 020 7679 6978; Fax: 44 020 7679 6973; E-mail: R.Chambers@ucl.ac.uk.
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