Inhibiting glycogen synthase kinase-3 decreases 12-O-tetradecanoylphorbol- 13-acetate-induced interferon-γ-mediated skin inflammation

Chia-Yuan Hsieh, Chia-Ling Chen, Cheng-Chieh Tsai, Wei-Ching Huang, Po-Chun Tseng, Yee-Shin Lin, Shun-Hua Chen, Tak-Wah Wong, Pui-Ching Choi, Chiou Feng Lin

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7 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)125-133
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
Publication statusPublished - Oct 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine


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