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.
Pasparakis
Manolis
M
Institute for Genetics, University of Cologne, Weyertal 121, D-50931 Cologne, Germany. pasparakis@embl-monterotondo.it
Courtois
Gilles
G
Hafner
Martin
M
Schmidt-Supprian
Marc
M
Nenci
Arianna
A
Toksoy
Atiye
A
Krampert
Monika
M
Goebeler
Matthias
M
Gillitzer
Reinhard
R
Israel
Alain
A
Krieg
Thomas
T
Rajewsky
Klaus
K
Haase
Ingo
I
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D051550:I-kappa B Kinase; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012871:Skin Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse