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

Nature. 2002 Jun 20;417(6891):861-6. doi: 10.1038/nature00820.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cell Division
  • Epidermis / drug effects*
  • Epidermis / enzymology*
  • Epidermis / metabolism
  • Epidermis / pathology
  • Gene Deletion*
  • I-kappa B Kinase
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Inflammation / chemically induced
  • Inflammation / enzymology
  • Inflammation / genetics
  • Inflammation / pathology
  • Keratinocytes / drug effects
  • Keratinocytes / enzymology
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Skin Diseases / chemically induced*
  • Skin Diseases / enzymology
  • Skin Diseases / genetics
  • Skin Diseases / pathology*
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • NF-kappa B
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse