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

M Pasparakis, G Courtois, M Hafner… - Nature, 2002 - nature.com
M Pasparakis, G Courtois, M Hafner, M Schmidt-Supprian, A Nenci, A Toksoy, M Krampert…
Nature, 2002nature.com
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,). IKK2 and NEMO are
necessary for NF-κB activation through pro-inflammatory signals,,,,,. IKK1 seems to be
dispensable for this function but controls epidermal differentiation independently of NF-κB,,,.
Previous studies suggested that NF-κB has a function in the growth regulation of epidermal …
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 , ). IKK2 and NEMO are necessary for NF-κB activation through pro-inflammatory signals,,,,,. IKK1 seems to be dispensable for this function but controls epidermal differentiation independently of NF-κB,,,. Previous studies suggested that NF-κB has a function in the growth regulation of epidermal keratinocytes,,. Mice lacking RelB or IκBα, as well as both mice and humans with heterozygous NEMO mutations, develop skin lesions,,,,,. However, the function of NF-κB 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-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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