IL-23 antagonizes UVR-induced immunosuppression through two mechanisms: reduction of UVR-induced DNA damage and inhibition of UVR-induced regulatory T cells

J Invest Dermatol. 2010 Feb;130(2):554-62. doi: 10.1038/jid.2009.274. Epub 2009 Sep 3.

Abstract

UVR-induced DNA damage is the major molecular trigger for photoimmunosuppression. The cytokines IL-12 and IL-18, which reduce DNA damage through induction of DNA repair, prevent UVR-induced immunosuppression. IL-12 but not IL-18 can break established UVR-induced immunotolerance through modulation of regulatory T cells (Treg). IL-23 is related to IL-12 by sharing the p40 subunit. Hence, we studied whether (i) IL-23 can reduce UVR-induced DNA damage and thereby prevent UVR-induced immunosuppression and (ii) can suppress the activity of Treg. IL-23 reduced UVR-induced apoptosis of keratinocytes. Injection of IL-23 into UVR-exposed mice diminished the number of apoptotic keratinocytes and the amounts of DNA damage. This was not observed in DNA repair-deficient xeroderma pigmentosum A knock-out mice (Xpa-KO mice), implying that IL-23 reduces DNA damage through induction of DNA repair. Similarly, UVR-mediated suppression of the induction of contact hypersensitivity was prevented on injection of IL-23 in wild-type but not in Xpa-KO mice. However, in contrast to IL-18, IL-23 inhibited the activity of UVR-induced Treg as demonstrated by adoptive transfer experiments. Our data indicate that IL-23, similar to IL-12 and IL-18, can reduce UVR-induced DNA damage and thereby prevent immunosuppression. IL-23 shares with IL-12 the still unique capacity to restore suppressed immune responses because of its effect on Treg.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • DNA Damage
  • Female
  • Immunosuppressive Agents / metabolism*
  • Interleukin-12 / metabolism*
  • Interleukin-18 / metabolism*
  • Interleukin-23 / metabolism*
  • Keratinocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Ultraviolet Rays
  • Xeroderma Pigmentosum / genetics

Substances

  • Immunosuppressive Agents
  • Interleukin-18
  • Interleukin-23
  • Interleukin-12