Hypoxia inducible factor-1α contributes to UV radiation-induced inflammation, epidermal hyperplasia and immunosuppression in mice

Photochem Photobiol Sci. 2012 Feb;11(2):309-17. doi: 10.1039/c1pp05265a. Epub 2011 Nov 3.

Abstract

Hypoxia inducible factor-1α (HIF-1α), a ubiquitous inducible oxygen-sensing transcription factor, promotes cell survival under hypoxic conditions, including the early pre-angiogenic period of tumorigenesis, and is known to contribute to many malignancies. However HIF-1α can also be activated by inflammatory mediators, and can activate inflammation-modulating proteins itself, including heme oxygenase-1 (HO-1) and the cytokine IL-6. Recently HIF-1α was reported to be induced by UVB (290-320 nm) radiation in cultured human keratinocytes, acting as a stress protein associated with the release of reactive oxygen species. In this in vivo murine study we demonstrate that HIF-1α protein is an early responder to UV radiation in the skin, and its activation can be attenuated by treating mice with its post-translational inhibitor, YC-1. Treatment with YC-1 following UV-irradiation of mice has revealed the involvement of HIF-1α in UV-induced inflammation, IL-6 production, and epidermal hyperplasia. In addition, upregulated cutaneous HIF-1α was found to be an important factor in the UV-suppression of T cell-mediated immunity, measured by contact hypersensitivity (CHS). The mechanism remains unclear, however it did not appear to involve the immunosuppressive cutaneous photoproduct cis-urocanic acid, but HIF-1α induction was inhibited by irradiation with photoimmune protective UVA (320-400 nm), implicating a negative correlation between the two stress proteins, HIF-1α and the photoimmune protective UVA responder HO-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dermatitis, Contact / etiology
  • Dermatitis, Contact / immunology
  • Dermatitis, Contact / metabolism
  • Edema / drug therapy
  • Edema / etiology
  • Edema / immunology
  • Edema / metabolism
  • Female
  • Gene Expression Regulation / radiation effects
  • Hyperplasia / etiology
  • Hyperplasia / immunology
  • Hyperplasia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immune Tolerance / radiation effects*
  • Indazoles / pharmacology
  • Indazoles / therapeutic use
  • Inflammation / etiology
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Skin / immunology
  • Skin / metabolism
  • Skin / pathology*
  • Skin / radiation effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / radiation effects
  • Ultraviolet Rays / adverse effects*

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indazoles
  • Interleukin-6
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole