RT Journal Article
SR Electronic
T1 Inhibiting Glycogen Synthase Kinase-3 Decreases 12-O-Tetradecanoylphorbol-13-Acetate-Induced Interferon-γ-Mediated Skin Inflammation
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.112.194100
DO 10.1124/jpet.112.194100
A1 Chia-Yuan Hsieh
A1 Chia-Ling Chen
A1 Cheng-Chieh Tsai
A1 Wei-Ching Huang
A1 Po-Chun Tseng
A1 Yee-Shin Lin
A1 Shun-Hua Chen
A1 Tak-Wah Wong
A1 Pui-Ching Choi
A1 Chiou-Feng Lin
YR 2012
UL http://jpet.aspetjournals.org/content/early/2012/07/06/jpet.112.194100.abstract
AB Glycogen synthase kinase (GSK)-3 facilitates interferon (IFN)-γ signaling. Because IFN-γ 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-γ -mediated ear skin inflammation. TPA (3 μg per ear) induced acute skin inflammation in the ears of C57BL/6 mice including edema, infiltration of granulocytes but not T cells, and IFN-γ receptor 1-mediated deregulation of intercellular adhesion molecule 1 (CD54). TPA/IFN-γ induced GSK-3 activation, which in turn activated signal transducer and activator of transcription 1. Inhibiting GSK-3 pharmacologically, by administering 6-bromoindirubin-3'-oxime (1.5 μ g per ear), and genetically, with lentiviral-based short-hairpin RNA, reduced TPA-induced acute skin inflammation but not T-cell infiltration. Notably, inhibiting GSK-3 decreased TPA-induced IFN-γ production and the nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ, 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-γ signaling but also to regulate IFN-γ production. Inhibiting GSK-3 may be a potential treatment strategy to prevent such effects.