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

Manolis Pasparakis (), Gilles Courtois, Martin Hafner, Marc Schmidt-Supprian, Arianna Nenci, Atiye Toksoy, Monika Krampert, Matthias Goebeler, Reinhard Gillitzer, Alain Israel, Thomas Krieg, Klaus Rajewsky and Ingo Haase
Additional contact information
Manolis Pasparakis: Institute for Genetics, University of Cologne
Gilles Courtois: Unité de Biologie Moléculaire de l'Expression Génique, URA 1773 CNRS, Institut Pasteur
Martin Hafner: University of Cologne
Marc Schmidt-Supprian: Institute for Genetics, University of Cologne
Arianna Nenci: EMBL Mouse Biology Programme
Atiye Toksoy: University of Würzburg
Monika Krampert: Institute for Cell Biology, ETH Hönggerberg, HPM D25
Matthias Goebeler: University of Würzburg
Reinhard Gillitzer: University of Würzburg
Alain Israel: Unité de Biologie Moléculaire de l'Expression Génique, URA 1773 CNRS, Institut Pasteur
Thomas Krieg: University of Cologne
Klaus Rajewsky: Institute for Genetics, University of Cologne
Ingo Haase: University of Cologne

Nature, 2002, vol. 417, issue 6891, 861-866

Abstract: Abstract The IκB kinase (IKK), consisting of the IKK1 and IKK2 catalytic subunits and the NEMO (also known as IKKγ) regulatory subunit, phosphorylates IκB proteins, targeting them for degradation and thus inducing activation of NF-κB (reviewed in refs 1, 2). IKK2 and NEMO are necessary for NF-κB activation through pro-inflammatory signals3,4,5,6,7,8. IKK1 seems to be dispensable for this function but controls epidermal differentiation independently of NF-κB9,10,11,12. Previous studies suggested that NF-κB has a function in the growth regulation of epidermal keratinocytes12,13,14. Mice lacking RelB or IκBα, as well as both mice and humans with heterozygous NEMO mutations, develop skin lesions7,8,15,16,17,18. However, the function of NF-κB in the epidermis remains unclear19. Here we used Cre/loxP-mediated gene targeting to investigate the function of IKK2 specifically in epidermal keratinocytes. IKK2 deficiency inhibits NF-κB 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, αβ T-cell-independent inflammatory response that develops in the skin shortly after birth. Our results suggest that the critical function of IKK2-mediated NF-κB activity in epidermal keratinocytes is to regulate mechanisms that maintain the immune homeostasis of the skin.

Date: 2002
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DOI: 10.1038/nature00820

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