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

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)125-133
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume343
Issue number1
DOIs
Publication statusPublished - 2012 Oct

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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