TNF is a potent cytokine with an important role in the regulation of a multitude of cellular responses and in coordinating immune and inflammatory reactions. TNF exerts its effects by binding to the TNFR1- and TNFR2-specific cell surface receptors, which activate a number of intracellular signaling cascades including the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways. Activation of NF-kappaB mediates many of the functions of TNF by transmitting information from the cell surface TNF receptors to the nucleus, where it coordinates a gene expression program that allows the cell to survive and elicit its responses. The intimate interplay of TNF with the NF-kappaB signaling pathway is highlighted by results obtained in transgenic and knockout mice with defects in NF-kappaB signaling components, where TNF has been shown to contribute to different pathologies observed in these mice. This chapter focuses on the function of TNF in pathologies induced by NF-kappaB deficiency and discusses the implications of these findings for our understanding of inflammatory diseases.

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