IKKβ Is Required for Prevention of Apoptosis Mediated by Cell-Bound but Not by Circulating TNFα

AbstractIκB kinase β (IKKβ) is required for NF-κB activation and suppression of TNFα-mediated liver apoptosis. To investigate how IKKβ suppresses apoptosis, we generated hepatocyte-specific Ikkβ knockout mice, IkkβΔhep, which exhibit little residual NF- κB activity but are healthy with normal liver function. Unexpectedly, IkkβΔhep mice are slightly more sensitive than controls to LPS-induced liver apoptosis but are highly susceptible to liver destruction following concanavalin A (ConA)-induced T cell activation. Unlike LPS, a potent inducer of circulating TNFα, ConA exerts cytotoxic effects through cell-bound TNFα, which activates type 1 and 2 TNF receptors (TNFR). While TNFR2 does not contribute to NF-κB activation, it is important for ConA-induced JNK activation, which is augmented by the absence of IKKβ. Using JNK-deficient mice we show that JNK is required for ConA-induced liver damage. Thus, the antiapoptotic function of IKKβ, which is most critical in situations that involve cell-bound TNFα, is mediated partially through attenuation of JNK activity