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TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2.

The I kappa B kinase (IKK), consisting of the IKK1 and IKK2 catalytic subunits and the NEMO (also known as IKK gamma) regulatory subunit, phosphorylates I kappa B proteins, targeting them for degradation and thus inducing activation of NF-kappa B (reviewed in refs 1, 2). IKK2 and NEMO are necessary for NF-kappa B activation through pro-inflammatory signals. IKK1 seems to be dispensable for this function but controls epidermal differentiation independently of NF-kappa B. Previous studies suggested that NF-kappa B has a function in the growth regulation of epidermal keratinocytes. Mice lacking RelB or I kappa B alpha, as well as both mice and humans with heterozygous NEMO mutations, develop skin lesions. However, the function of NF-kappa B in the epidermis remains unclear. Here we used Cre/loxP-mediated gene targeting to investigate the function of IKK2 specifically in epidermal keratinocytes. IKK2 deficiency inhibits NF-kappa B activation, but does not lead to cell-autonomous hyperproliferation or impaired differentiation of keratinocytes. Mice with epidermis-specific deletion of IKK2 develop a severe inflammatory skin disease, which is caused by a tumour necrosis factor-mediated, alpha beta T-cell-independent inflammatory response that develops in the skin shortly after birth. Our results suggest that the critical function of IKK2-mediated NF-kappa B activity in epidermal keratinocytes is to regulate mechanisms that maintain the immune homeostasis of the skin.

Pubmed ID: 12075355

Authors

  • Pasparakis M
  • Courtois G
  • Hafner M
  • Schmidt-Supprian M
  • Nenci A
  • Toksoy A
  • Krampert M
  • Goebeler M
  • Gillitzer R
  • Israel A
  • Krieg T
  • Rajewsky K
  • Haase I

Journal

Nature

Publication Data

June 20, 2002

Associated Grants

None

Mesh Terms

  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cell Division
  • Epidermis
  • Gene Deletion
  • I-kappa B Kinase
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Inflammation
  • Keratinocytes
  • Mice
  • Mice, Knockout
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • RNA, Messenger
  • Skin Diseases
  • Tumor Necrosis Factor-alpha