ABSTRACT
Doctorate School Biomedicine and Immunological Science, Section of Clinical Pharmacology, Dept. of Clinical Medicine and Immunological Sciences - University of Siena, Italy.
Systemic sclerosis (SSc) is a connective tissue disease characterized by exaggerated collagen deposition in the skin and visceral organs [1].
Adenosine A2A receptor stimulation (A2Ar) promotes dermal fibrosis [2,5], while the cannabinoid system modulates fibrogenesis in-vitro and in animal models of SSc [6,11]. Moreover, evidence in central nervous system suggests that the A2A and the cannabinoid (CB1) receptors may physically and functionally interact [12,13].
On this basis, we investigated the A2Ar expression and function in modulating collagen biosynthesis from SSc dermal fibroblasts, also analyzing the cross-talk with the cannabinoid receptors.
In sclerodermic cells, A2Ar expression (RT-PCR, Western blotting), and the effects of A2A agonists and/or antagonists on collagen biosynthesis (EIA, Western blotting) were evaluated. The putative physical and functional interactions between the A2A and the cannabinoid receptors were respectively assessed by co-immunoprecipitation, and co-incubating the cells with the unselective cannabinoid agonist WIN-55,212, and the selective A2A antagonist ZM-241385.
In SSc fibroblasts: (i) A2Ar is overexpressed, and its occupancy with the selective agonist CGS-21680 increases collagen production, myofibroblast trans-differentiation and ERK-1/2 phosphorylation; (ii) the A2Ar forms an heteromer with the cannabinoid CB1 receptor, and (iii) the unselective cannabinoid receptor stimulation with a per se ineffective dose of WIN55,212-2, results in a marked anti-fibrotic effect after the A2Ar blockage.
In conclusion, A2Ar stimulation induces a pro-fibrotic phenotype in SSc dermal fibroblasts, either directly, and indirectly by activating the CB1 cannabinoid receptor. These findings increase our knowledge of the pathophysiology of sclerodermic fibrosis also further suggesting a new therapeutic approach to the disease.
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