Glycogen synthase kinase-3 facilitates IFN-γ-mediated phorbol ester-induced skin inflammation (54.25)

Abstract

Abstract Activation of glycogen synthase kinase (GSK)-3 facilitates IFN-γ signaling, and IFN-γ generation is positively correlated with disease severity in inflammatory skin diseases, such as psoriasis and atopic dermatitis. In this study, we investigated a pathogenic role for GSK-3 in phorbol ester (12-O-tetradecanoylphorbol-13-acetate; TPA)-induced IFN-γ-mediated skin inflammation. TPA induced acute skin inflammation in the ears of C57BL/6 mice, including edema, the infiltration of granulocytes but not T cells, and the deregulation of adhesion molecule CD54 expression, in an IFN-γ receptor (IFNGR) 1-regulated manner. TPA/IFN-γ induced GSK-3 activation and caused the activation and expression of signal transducers and activators of transcription 1 in a GSK-3-regulated manner. Inhibiting GSK-3 through either pharmacological inhibition or a genetic approach using lentiviral-based short hairpin RNA reduced acute TPA-induced skin inflammation, but not T cell infiltration. Notably, inhibiting GSK-3 decreased the TPA-induced IFN-γ production as well as the nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ, in CD3+ T cells. In chronic TPA-induced skin inflammation, inhibiting GSK-3 attenuated epidermis hyperproliferation and dermis angiogenesis. These results demonstrate the dual and indispensable role of GSK-3 in TPA-induced skin inflammation by facilitating IFN-γ signaling.