Anales RANF

P.82 THERAPEUTIC POTENTIAL OF ADENOSINE IN INFLAMMATORY SKIN DISEASES A. Marín-Castejón 1 , M. Marco 1 , J. Arasa, R.M. Andrés, M.C. Terencio 1 , M.C. Montesinos 1 1 . University of Valencia, Valencia, Spain Inflammatory skin diseases are characterized by an increased epidermal turnover and altered immune and inflammatory responses. Since adenosine, through the interaction of its receptors, regulates inflammation and immunity, we sought to study the expression and function of adenosine receptors in keratinocytes and in an inflammatory model of epidermal hyperplasia. We observed that A 2B subtype is the most prominently expressed in epidermal cells from healthy donors, followed by the A 2A receptor; neither mRNA levels for A 1 nor A 3 receptors were detected. Activation of A 2B receptors induced cell-cycle arrest through the increase of intracellular calcium. In contrast, A 2A activation induced keratinocyte proliferation via p38-mitogen-activated protein kinase activation. We found an altered pattern of Adenosine receptors in epidermis from psoriatic patients, consisting in decreased A 2B and increased A 2A receptor expression, which was reproduced in keratinocytes exposed to diverse inflammatory cytokines. In the murine model of skin hyperplasia induced by of 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 nmol/site) for three consecutive days, topical pretreatment with the A 2A agonist CGS-21680 (5 µg/site) had a profound anti-inflammatory response and prevented the epidermal hyperplasia, while promoting collagen deposition in dermis. The A 2B agonist BAY60- 6583 (1-10 µg/site) also improved the severity of skin lesions and diminished in a dose- dependent manner IL-1 β , CXCL-1 and IL-6 levels determined in skin homogenates. Interestingly, the A 2B antagonist PSB-1115 (10-50 µg/site) not only reversed the beneficial effect of BAY on the skin, but also worsened the lesions, enhancing the inflammatory response and inducing a clear degradation of epidermal layer. Our results suggest that adenosine plays an important role regulating epidermal homeostasis, and thus may constitute an interesting therapeutic strategy in inflammatory hyperproliferative skin diseases such as psoriasis.