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Research ArticleInflammation, Immunopharmacology, and Asthma

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 and Chiou-Feng Lin
Journal of Pharmacology and Experimental Therapeutics October 2012, 343 (1) 125-133; DOI: https://doi.org/10.1124/jpet.112.194100
Chia-Yuan Hsieh
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Chia-Ling Chen
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Cheng-Chieh Tsai
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Wei-Ching Huang
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Po-Chun Tseng
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Yee-Shin Lin
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Shun-Hua Chen
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Tak-Wah Wong
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Pui-Ching Choi
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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Chiou-Feng Lin
Institute of Clinical Medicine (C.-Y.H., C.-C.T., W.-C.H., P.-C.T., P.-C.C., C.-F.L.), Center of Infectious Disease and Signaling Research (C.-L.C., Y.-S.L., C.-F.L.), Institute of Basic Medical Sciences (C.-C.T., Y.-S.L., S.-H.C., C.-F.L.), and Departments of Microbiology and Immunology (Y.-S.L., S.-H.C., C.-F.L.), Dermatology (T.-W.W.), and Biochemistry and Molecular Biology (T.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan (C.-C.T.)
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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.

Footnotes

  • This work was supported by the National Science Council of Taiwan [Grants NSC 96-2320-B-006-018-MY3; NSC 99-2320-B-006-004-MY3].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.194100.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    Th
    T helper
    GSK-3
    glycogen synthase kinase-3
    pGSK-3
    phospho-GSK-3
    pGS
    phospho-glycogen synthase
    IFN
    interferon
    IFNGR1
    IFN-γ receptor type 1
    Ifngr1(−/−)
    IFN-γ receptor 1-deficient
    T-bet
    T-box transcription factor Tbx21
    Jak
    Janus kinase
    STAT
    signal transducer and activator of transcription
    pSTAT1
    phospho-STAT1
    IRF-1
    IFN Regulatory Factor 1
    PBS
    phosphate-buffered saline
    DMSO
    dimethyl sulfoxide
    TPA
    12-O-tetradecanoylphorbol-13-acetate
    BIO
    6-bromoindirubin-3′-oxime
    shRNA
    short hairpin RNA
    shLuc
    shRNA-luciferase
    DAPI
    4′,6-diamidino-2-phenylindole
    H&E
    hematoxylin and eosin
    AEC
    3-amino-9-ethylcarbazole
    RBG
    red/green/blue
    IOD
    integrated optical density
    IL
    interleukin.

  • Received March 8, 2012.
  • Accepted July 5, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 1
1 Oct 2012
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Research ArticleInflammation, Immunopharmacology, and Asthma

GSK-3 Facilitates 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 and Chiou-Feng Lin
Journal of Pharmacology and Experimental Therapeutics October 1, 2012, 343 (1) 125-133; DOI: https://doi.org/10.1124/jpet.112.194100

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Research ArticleInflammation, Immunopharmacology, and Asthma

GSK-3 Facilitates 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 and Chiou-Feng Lin
Journal of Pharmacology and Experimental Therapeutics October 1, 2012, 343 (1) 125-133; DOI: https://doi.org/10.1124/jpet.112.194100
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