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

J Pharmacol Exp Ther. 2012 Oct;343(1):125-33. doi: 10.1124/jpet.112.194100. Epub 2012 Jul 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Dermatitis / drug therapy*
  • Dermatitis / enzymology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Interferon-gamma / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oximes / pharmacology
  • Oximes / therapeutic use
  • Receptors, Interferon / deficiency
  • Tetradecanoylphorbol Acetate / antagonists & inhibitors*
  • Tetradecanoylphorbol Acetate / toxicity*

Substances

  • 6-bromoindirubin-3'-oxime
  • Indoles
  • Oximes
  • Receptors, Interferon
  • interferon gamma receptor
  • Interferon-gamma
  • Glycogen Synthase Kinase 3
  • Tetradecanoylphorbol Acetate