Abstract
IntroductionAdenosine, acting through the A2A receptor, 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 A2A receptors is increased in scleroderma fibroblasts, we examined the mechanisms by which the A2A receptor produces its fibrogenic effects.MethodsThe effects of A2A receptor 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 A2A receptor stimulation on CTGF and TGF-β1 expression are also examined.ResultsA2A receptor occupancy suppresses the expression of Fli1 by dermal fibroblasts. A2A receptor activation induces the secretion of CTGF by dermal fibroblasts, and neutralization of CTGF abrogates the A2A receptor-mediated enhancement of collagen type I production. A2AR activation, however, resulted in a decrease in TGF-β1 protein release.ConclusionsOur results suggest that Fli1 and CTGF are important mediators of the fibrogenic actions of adenosine and the use of small molecules such as adenosine A2A receptor antagonists may be useful in the therapy of dermal fibrosis in diseases such as scleroderma.
Highlights
Adenosine, acting through the A2A receptor, promotes tissue matrix production in the skin and the liver and induces the development of dermal fibrosis and cirrhosis in murine models
Adenosine A2A receptor activation suppresses friend leukemia integration-1 (Fli1) expression in human dermal fibroblasts We have previously demonstrated that adenosine A2A receptor activation increases collagen production in dermal fibroblasts, including type I and III collagens [6], the molecular events involved are unclear
Since suppression of Fli1 expression has been associated with increased collagen synthesis [16], we investigated whether adenosine A2A receptor activation results in alteration of Fli1 message expression
Summary
Adenosine, acting through the A2A receptor, 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 A2A receptors is increased in scleroderma fibroblasts, we examined the mechanisms by which the A2A receptor produces its fibrogenic effects. Adenosine and adenosine A2A receptors regulate the function of many cell types that stimulate matrix production and fibrosis indirectly, we have reported that stimulation of the A2A receptor on matrix producing fibroblasts in the skin and stellate cells in the liver directly stimulates collagen production [6,7]. The adenosine A2A receptor is a GS-linked receptor that stimulates cAMP accumulation and other downstream signals that mediate activation of collagen production by fibroblasts and stellate cells. A number of downstream signals play a role in the stimulation of collagen production by stellate cells including activation of the downstream kinases ERK1/2 (linked to collagen type I production) and p38 MAPKinase (linked to collagen type III production) [12]
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