Adenosine A2Areceptors promote collagen production by a Fli1- and CTGF-mediated mechanism

Abstract

Introduction: Adenosine, acting through the A2Areceptor, promotes tissue matrix production in the skin and the liver and induces the development of dermal fibrosis and cirrhosis in murine models. Since expression of A2Areceptors is increased in scleroderma fibroblasts, we examined the mechanisms by which the A2Areceptor produces its fibrogenic effects. Methods: The effects of A2Areceptor ligation on the expression of the transcription factor, Fli1, a constitutive repressor for the synthesis of matrix proteins, such as collagen, is studied in dermal fibroblasts. Fli1 is also known to repress the transcription of CTGF/CCN2, and the effects of A2Areceptor stimulation on CTGF and TGF-β1 expression are also examined.Results: A2Areceptor occupancy suppresses the expression of Fli1 by dermal fibroblasts. A2Areceptor activation induces the secretion of CTGF by dermal fibroblasts, and neutralization of CTGF abrogates the A2Areceptor-mediated enhancement of collagen type I production. A2AR activation, however, resulted in a decrease in TGF-β1 protein release.Conclusions: Our results suggest that Fli1 and CTGF are important mediators of the fibrogenic actions of adenosine and the use of small molecules such as adenosine A2Areceptor antagonists may be useful in the therapy of dermal fibrosis in diseases such as scleroderma. © 2013 Chan et al.; licensee BioMed Central Ltd.