Adenosine A2A Receptor Promotes Collagen Type III Synthesis Via β‐Catenin Activation in Human Dermal Fibroblasts

:Background and Purpose Adenosine 2A receptor (A2AR) stimulation promotes collagen type I and type III (Col1 and Col3) synthesis, mediators of fibrosis and scarring. A2AR modulates collagen balance via cAMP/PKA/p38-MAPK/AKT. Wnt signaling is important in fibrosis and cAMP and Wnt pathways converge. Since A2AR is Gs-linked increasing cAMP, we determined whether A2AR and Wnt signaling interact. Experimental Approach Total β-catenin, de-phosphorylated β-catenin (canonical activation, de-phospho β-catenin), and phosphorylated β-catenin at Ser552 (non-canonical activation, p-Ser552 β-catenin) levels were determined in primary human dermal fibroblast, cytosol and nucleus by western blot and fluorescence microscopy after stimulation by A2AR-selective agonist CGS21680, with/without A2AR-selective antagonist (SCH582611) pretreatment. β-catenin was knocked down by transfection with scrambled-siRNA or specific-siRNA, and Col1 and Col3 levels determined by western blot. Key Results CGS21680 stimulation rapidly (15 min) increased cellular β-catenin to 174 ± 23% of control (n = 6, P   0.05) and p-Ser552 β-catenin (220 ± 22% of control, n = 6, P < 0.05) were increased. CGS21680 stimulated translocation of total, de-phospho, and p-Ser552 β-catenin to the nucleus. A2AR-stimulation increased Col1 synthesis similarly in β-catenin knockdown and scrambled cells. However, β-catenin knockdown abrogated the A2AR-stimulated increments in Col3 synthesis by 73% (66 ± 14% vs. 18 ± 16% increase of Col3, n = 8, P < 0.05). Conclusions and Implications A2AR stimulation promotes Col3 synthesis via canonical and non-canonical β-catenin activation, consistent with the role of A2AR in dermal fibrosis and scarring.