期刊
IMMUNITY
卷 19, 期 5, 页码 725-737出版社
CELL PRESS
DOI: 10.1016/S1074-7613(03)00301-7
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资金
- NIAID NIH HHS [AI43477] Funding Source: Medline
- NIEHS NIH HHS [ES10337, ES06376] Funding Source: Medline
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI043477] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [P42ES010337, R01ES006376] Funding Source: NIH RePORTER
IkappaB kinase beta (IKKbeta) is required for NF-kappaB activation and suppression of TNFalpha-mediated liver apoptosis. To investigate how IKKbeta suppresses apoptosis, we generated hepatocyte-specific Ikkbeta knockout mice, IkkbetaDelta(hep), which exhibit little residual NF-kappaB activity but are healthy with normal liver function. Unexpectedly, Ikkbeta(Deltahep),P 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 TNFalpha, ConA exerts cytotoxic effects through cell-bound TNFalpha, which activates type 1 and 2 TNF receptors (TNFR). While TNFR2 does not contribute to NF-kappaB activation, it is important for ConA-induced JNK activation, which is augmented by the absence of IKKbeta. Using JNK-deficient mice we show,that JNK is required for ConA-induced liver damage. Thus, the antiapoptotic function of IKKbeta, which is most-critical in situations that involve cell-bound TNFalpha, is mediated partially through attenuation of JNK activity.
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