Down-regulation of the A3 adenosine receptor in human mast cells upregulates mediators of angiogenesis and remodeling

• Activated human mast cell A3R upregulates tissue remodeling gene expression.
• Dexamethasone potentiates the A3R mediated upregulation of tissue remodeling genes.
• Activated human mast cell A3R down regulates its own expression.
• Knockdown of the A3R in human mast cells upregulates tissue remodeling genes.

Adenosine activated mast cells have been long implicated in allergic asthma and studies in rodent mast cells have assigned the A3 adenosine receptor (A3R) a primary role in mediating adenosine responses. Here we analyzed the functional impact of A3R activation on genes that are implicated in tissue remodeling in severe asthma in the human mast cell line HMC-1 that shares similarities with lung derived human mast cells. Quantitative real time PCR demonstrated upregulation of IL6, IL8, VEGF, amphiregulin and osteopontin. Moreover, further upregulation of these genes was noted upon the addition of dexamethasone. Unexpectedly, activated A3R down regulated its own expression and knockdown of the receptor replicated the pattern of agonist induced gene upregulation. This study therefore identifies the human mast cell A3R as regulator of tissue remodeling gene expression in human mast cells and demonstrates a heretofore-unrecognized mode of feedback regulation that is exerted by this receptor.