ASB-16165

Possible role of phosphodiesterase 7A (PDE7A) in skin inflammation was examined using ASB16165, a specific inhibitor for PDE7A. Epicutaneous application of phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ear resulted in induction of skin edema, and topical treatment with ASB16165 inhibited the induction of skin edema in a dose-dependent manner. The TPA challenge also increased the level of TNF-alpha at the application site, and the ASB16165 treatment reduced the TNF-alpha level in the skin. In addition, ASB16165 suppressed the production of TNF-alpha by human keratinocytes stimulated in vitro with TPA and calcium ionophore. Forskolin, an activator of adenylyl cyclase, as well as dibutyryl cAMP also showed inhibitory effect on the TNF-alpha production in the cells, suggesting involvement of cAMP in TNF-alpha generation. These results demonstrate that PDE7A might regulate TNF-alpha production in keratinocytes in a cAMP-dependent fashion. As immunostaining analysis revealed that PDE7A is expressed in the epidermis and TNF-alpha is known to contribute to the TPA-induced edema, it is possible that the inhibitory effect of ASB16165 on skin edema in mouse TPA-induced dermatitis model is mediated by suppression of TNF-alpha production. This is the first report suggesting the association of PDE7A with the function of keratinocytes. ASB16165 will be useful as an agent for skin inflammation in which TNF-alpha plays a pathogenic role (e.g. psoriasis).

Phosphodiesterase 7A (PDE7A) has been suggested to be involved in activation of T lymphocytes. In the present study, a possible involvement of PDE7A in function of preactivated T cells (i.e. T lymphoblasts) was investigated using ASB16165, an inhibitor for PDE7A. ASB16165, which has an IC50 value of 15 nM for human PDE7A, suppressed IL-12-induced IFN-gamma production by T lymphoblasts which have been prepared by stimulating mouse T cells with anti-CD3 antibody. In the same experiment, rolipram, a PDE4-specific inhibitor, showed similar effect, while calcineurin antagonist FK506 did not. Forskolin (an adenylyl cyclase activator) and dibutyryl cAMP also inhibited the IL-12-induced IFN-gamma synthesis. Rp-8-Br-cAMPS, an inhibitor of protein kinase A (PKA), reduced the suppressive effect of ASB16165 on the IFN-gamma production by T lymphoblasts. The rescue of IFN-gamma production by Rp-8-Br-cAMPS was also observed in the inhibition by rolipram and forskolin. These findings suggest that PDE7A may regulate function of activated T cells in a cAMP/PKA-dependent manner, and that PDE4 might share the role. The data in our study also indicate that PDE7 inhibitors such as ASB16165 will be beneficial for the patients with immunological disorders.