Adenosine induces IL-31 secretion by T-helper 2 cells: Implication for the effect of adenosine on atopic dermatitis and its therapeutic strategy.

ABSTRACT

Interleukin (IL)-31 is a recently-identified cytokine with a well-defined role in the pathogenesis of pruritus. Previously, we reported that adenosine upregulates IL-17A secretion by T-helper (Th)17 cells; however, the effect of adenosine on T cell subsets other than Th17 remains unclear. In this report, we show that adenosine upregulated production of IL-31 by cluster of differentiation (CD)4+ T cells. IL-31 was also upregulated by administration of an adenosine A2a receptor (A2aR) agonist (PSB0777), and adenosine-mediated IL-31 production was inhibited by an A2aR antagonist (istradefylline). Production of Th2-related cytokines (IL-4, IL-10, and IL-13) by CD4+ T cells showed the same tendency. Immune subset analyses revealed that adenosine upregulated IL-31 secretion by CD4+ chemokine receptor 3high T cells, and that Th2 cells differentiated from naïve CD4+ T cells. Administration of istradefylline to mice with atopic dermatitis suppressed the symptoms, suggesting that A2aR antagonists are an effective treatment for inflammatory dermatitis. Taken together, the results indicate that adenosine upregulates secretion of Th2-related cytokines by effector T cells in the skin, thereby triggering atopic dermatitis and associated pruritus.