Female Mice Heterozygous for IKKγ/NEMO Deficiencies Develop a Dermatopathy Similar to the Human X-Linked Disorder Incontinentia Pigmenti

Abstract

IKK gamma/NEMO is the essential regulatory subunit of the I kappa B kinase (IKK), encoded by an X-linked gene in mice and humans. It is required for NF-kappa B activation and resistance to TNF-induced apoptosis. Female mice heterozygous for Ikk gamma/Nemo deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis. Although Ikk gamma+/- females eventually recover, Ikk gamma- males die in utero. These symptoms and inheritance pattern are very similar to those of incontinentia pigmenti (IP), a human genodermatosis, synthenic with the IKK gamma/NEMO locus. Indeed, biopsies and cells from IP patients exhibit defective IKK gamma/NEMO expression but normal expression of IKK catalytic subunits. This unique self-limiting disease, the first to be genetically linked to the IKK signaling pathway, is dependent on X-chromosome inactivation. We propose that the IKK gamma/NEMO-deficient cells trigger an inflammatory reaction that eventually leads to their death.

Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-κB activation

“…Retrovirus constructs containing C-terminal Flag epitope-tagged HHV8 vFLIP (K13-Flag) were generated in MSCVneo and MIGR1-based retroviral vectors (Pear et al, 1998) and amphotropic viruses generated and used for infection as described previously . The IKKaÀ/À and IKKbÀ/À mouse embryonic fibroblast cells were generated in Dr Inder Verma's laboratory (Li et al, 1999a, b) and IKKg/NEMOÀ/À cells were generated in Dr Michael Karin's laboratory (Makris et al, 2000). These cells were kindly provided by Dr Richard Gaynor and were maintained in DMEM supplemented with 10% FBS.…”

Traf6 is essential for murine tooth cusp morphogenesis

“…Eda signaling and Troy are believed to be mediated by NF-B (Kojima et al, 2000;Yan et al, 2000;Kumar et al, 2001). Indeed mutations in certain components of the NF-B pathway have molar cusp abnormalities (Hu et al, 1999b;Li et al, 1999;Takeda et al, 1999;Makris et al, 2000;Zonana et al, 2000;Dö ffinger et al, 2001; Ohazama et al, manuscript submitted for publication). Trafs are known mediators of TNF signaling, acting as intracellular adaptor molecules that bind to TNF receptors.…”

Amelioration of acute inflammation by systemic administration of a cell‐permeable peptide inhibitor of NF‐κB activation

“…Gene-targeting experiments have clearly demonstrated that NEMO is absolutely critical for proinflammatory activation of IKK. In fact, NEMO-deficient cells lack detectable NF-B binding activity in response to TNF␣, IL-1␤, and LPS, and they do not show stimulusdependent I B kinase activity (9)(10)(11).…”