Inhibiting Glycogen Synthase Kinase-3 Decreases 12-O-Tetradecanoylphorbol-13-Acetate-Induced Interferon-γ-Mediated Skin Inflammation

Glycogen synthase kinase-3 (GSK-3) facilitates interferon (IFN)-gamma signaling. Because IFN-gamma is involved in inflammatory skin diseases, such as psoriasis, the aim of this study was to investigate the pathogenic role of GSK-3 in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IFN-gamma-mediated ear skin inflammation. TPA (3 mu g per ear) induced acute skin inflammation in the ears of C57BL/6 mice, including edema, infiltration of granulocytes but not T cells, and IFN-gamma receptor 1-mediated deregulation of intercellular adhesion molecule 1 (CD54). TPA/IFN-gamma induced GSK-3 activation, which in turn activated signal transducer and activator of transcription 1. Inhibiting GSK-3 pharmacologically, by administering 6-bro-moindirubin-3'-oxime (1.5 mu g per ear), and genetically, with lentiviral-based short-hairpin RNA, reduced TPA-induced acute skin inflammation but not T-cell infiltration. It is noteworthy that inhibiting GSK-3 decreased TPA-induced IFN-gamma production and the nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-gamma, in CD3-positive T cells. In chronic TPA-induced skin inflammation, inhibiting GSK-3 attenuated epidermis hyperproliferation and dermis angiogenesis. These results demonstrate the dual role of GSK-3 in TPA-induced skin inflammation that is not only to facilitate IFN-gamma signaling but also to regulate IFN-gamma production. Inhibiting GSK-3 may be a potential treatment strategy for preventing such effects.