title: Inhibiting glycogen synthase kinase-3 decreases 12-O-tetradecanoylphorbol-13-acetate-induced interferon-γ-mediated skin inflammation.
abstract: Glycogen synthase kinase-3 (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 μg 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-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 for preventing such effects.
authors: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Chia-Yuan
authors: CY
authors: Hsieh
authors: Chia-Ling
authors: CL
authors: Chen
authors: Cheng-Chieh
authors: CC
authors: Tsai
authors: Wei-Ching
authors: WC
authors: Huang
authors: Po-Chun
authors: PC
authors: Tseng
authors: Yee-Shin
authors: YS
authors: Lin
authors: Shun-Hua
authors: SH
authors: Chen
authors: Tak-Wah
authors: TW
authors: Wong
authors: Pui-Ching
authors: PC
authors: Choi
authors: Chiou-Feng
authors: CF
authors: Lin
mesh_terms: D000818:Animals; D002460:Cell Line; D003872:Dermatitis / Q000188:drug therapy* / Q000201:enzymology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D017471:Receptors, Interferon / Q000172:deficiency; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000096743:Interferon gamma Receptor
chemical_list: D038362:Glycogen Synthase Kinase 3; D007211:Indoles; D007371:Interferon-gamma; D010091:Oximes; D017471:Receptors, Interferon; D013755:Tetradecanoylphorbol Acetate; D000096743:Interferon gamma Receptor; C483321:6-bromoindirubin-3'-oxime