Constitutive NF-κB activation, enhanced granulopoiesis, and neonatal lethality in IκBα-deficient mice

Abstract

Transcription factors belonging to the NF-κB family are controlled by inhibitory IκB proteins, mainly IκBα and IκBβ. Apparently normal at birth, IκBα^(-/-) mice exhibit severe runting, skin defects, and extensive granulopoiesis postnatally, typically dying by 8 days. Hematopoietic tissues from these mice display elevated levels of both nuclear NF-κB and mRNAs of some, but not all, genes thought to be regulated by NF-κB. NF-κB elevation results in these phenotypic abnormalities because mice lacking both IκBα and the p50 subunit of NF-κB show a dramatically delayed onset of abnormalities. In contrast to hematopoietic cells, IκBα^(-/-) embryonic fibroblasts show minimal constitutive NF-κB, as well as normal signal-dependent NF-κB activation that is concomitant with IκBβ degradation. Our results indicate that Iκbβ, but not IκBα, is required for the signal-dependent activation of NF-κB in fibroblasts. However, IκBα is required for the postinduction repression of NF-κB in fibroblasts. These results define distinct roles for the two forms of IκB and demonstrate the necessity for stringent control of NF-κB.

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