STAT3-dependent effects of IL-22 in human keratinocytes are counterregulated by sirtuin 1 through a direct inhibition of STAT3 acetylation

FASEB J. 2011 Mar;25(3):916-27. doi: 10.1096/fj.10-172288. Epub 2010 Nov 23.

Abstract

IL-22 has a pathogenetic role in psoriasis, where it is responsible for the altered proliferation and differentiation of keratinocytes and induces inflammatory molecules. The IL-22-induced effects are mediated by STAT3, whose activity is proportional to acetylation in lysine (Lys)685 and phosphorylation in tyrosine (Tyr)705. Lys 685 acetylation of STAT3 is inhibited by sirtuin (SIRT)1, a class III deacetylase promoting keratinocyte differentiation. Due to the opposite effects of IL-22 and SIRT1, we investigated whether IL-22-induced effects in keratinocytes could be regulated by SIRT1 through control of STAT3. We found that SIRT1 opposes the IL-22-induced STAT3 activity by deacetylating STAT3 and reducing STAT3 Tyr705 phosphorylation. By controlling STAT3, SIRT1 also influences the IL-22-induced expression of molecules involved in proliferation and inflammation as well as proliferation and migration processes in cultured keratinocytes. Although SIRT1 levels were similar in keratinocytes of healthy individuals and patients with psoriasis, they were reduced in psoriatic skin lesions, with the lymphokine IFN-γ inhibiting SIRT1 expression. Concomitantly, IFN-γ enhanced basal acetylation of STAT3 and its phosphorylation induced by IL-22. In conclusion, STAT3-dependent IL-22 signaling and effects in keratinocytes are negatively regulated by SIRT1. In skin affected by psoriasis, SIRT1 is down-regulated by IFN-γ, which thus renders psoriatic keratinocytes more prone to respond to IL-22.

MeSH terms

  • Acetylation / drug effects
  • Adult
  • Cell Division / physiology
  • Cell Movement / physiology
  • Cells, Cultured
  • Dermatitis / immunology
  • Dermatitis / metabolism
  • Histone Deacetylases / metabolism
  • Humans
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Interleukins / metabolism*
  • Keratinocytes / cytology
  • Keratinocytes / immunology
  • Keratinocytes / metabolism*
  • Phosphorylation / physiology
  • Protein Processing, Post-Translational / physiology
  • Psoriasis / immunology
  • Psoriasis / metabolism*
  • RNA, Small Interfering
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / immunology
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*

Substances

  • Interleukins
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Interferon-gamma
  • SIRT1 protein, human
  • Sirtuin 1
  • Histone Deacetylases
  • histone deacetylase 3
  • interleukin-22