TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2 (original) (raw)

Nature volume 417, pages 861–866 (2002) Cite this article

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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.

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A Correction to this paper has been published: https://doi.org/10.1038/s41586-025-09789-z

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Acknowledgements

We thank B. Hampel, A. Egert, A. Leinhaas, R. Pofahl, A. Arora, R. Knaup, C. Bessia and the members of the laboratory for skin histopathology of the University of Cologne for technical support. We also thank J. Peschon, G. Kollias and S. Werner for critical reading of the manuscript, G. Mahrle for discussions and F. M. Watt and T. Magin for providing antibodies. M.P. was supported by fellowships from EMBO and the Leukemia and Lymphoma Society; I.H. received grants from the German Ministry of Education and Research and from the Köln Fortune Program. This work was supported by grants from the Cologne Centre for Molecular Medicine (ZMMK) to W. Muller and K.R, from Ligue contre le Cancer (Equipe Labellisée) to A.I., and from the Körber Foundation, the European Union and the Deutsche Forschungsgemeinschaft to K.R.

Author information

Author notes

  1. Marc Schmidt-Supprian & Klaus Rajewsky
    Present address: Center for Blood Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, 02115, USA
  2. Martin Hafner
    Present address: German Research Centre for Biotechnology, Mascheroder Weg 1, 38124, Braunschweig, Germany

Authors and Affiliations

  1. Institute for Genetics, University of Cologne, Weyertal 121, D-50931, Cologne, Germany
    Manolis Pasparakis, Marc Schmidt-Supprian & Klaus Rajewsky
  2. EMBL Mouse Biology Programme, via Ramarini 32, I-00016, Monterotondo, Italy
    Manolis Pasparakis & Arianna Nenci
  3. Unité de Biologie Moléculaire de l'Expression Génique, URA 1773 CNRS, Institut Pasteur, 25 rue du Dr Roux, 75724, Cedex 15, Paris, France
    Gilles Courtois & Alain Israel
  4. Department of Dermatology and Center for Molecular Medicine, University of Cologne, Joseph-Stelzmann Strasse 9, D-50924, Cologne, Germany
    Martin Hafner, Thomas Krieg & Ingo Haase
  5. Department of Dermatology, University of Würzburg, Josef-Schneider Strasse 2, 97080, Würzburg, Germany
    Atiye Toksoy, Matthias Goebeler & Reinhard Gillitzer
  6. Institute for Cell Biology, ETH Hönggerberg, HPM D25, CH-8093, Zürich, Switzerland
    Monika Krampert
  7. Center for Blood Research, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, 02115, USA
    Martin Hafner, Atiye Toksoy, Matthias Goebeler & Reinhard Gillitzer
  8. German Research Centre for Biotechnology, Mascheroder Weg 1, 38124, Braunschweig, Germany
    Marc Schmidt-Supprian, Atiye Toksoy, Matthias Goebeler, Reinhard Gillitzer & Klaus Rajewsky

Authors

  1. Manolis Pasparakis
  2. Gilles Courtois
  3. Martin Hafner
  4. Marc Schmidt-Supprian
  5. Arianna Nenci
  6. Atiye Toksoy
  7. Monika Krampert
  8. Matthias Goebeler
  9. Reinhard Gillitzer
  10. Alain Israel
  11. Thomas Krieg
  12. Klaus Rajewsky
  13. Ingo Haase

Corresponding author

Correspondence toManolis Pasparakis.

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The authors declare that they have no competing financial interests.

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Pasparakis, M., Courtois, G., Hafner, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2.Nature 417, 861–866 (2002). https://doi.org/10.1038/nature00820

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