NF- B Activation by Tumor Necrosis Factor and Interleukin-1

Tumor necrosis factor (TNF) and interleukin-1 (IL-1)are two potent pro-inflammatory cytokines that are synthesized and released mainly by activated macrophages.TNF and IL-1 signal through widely distributed cell surface receptors to initiate signaling cascades that result inthe transcriptional activation of genes encoding many inflammatory proteins, including cytokines, chemokines,acute phase proteins, and pro-inflammatory enzymes(Barnes and Karin 1997). These transcriptional effectsare mediated largely by the transfection factors NF-κBand AP-1, which bind to and activate the promoters ofmany cytokine-responsive genes. Although TNF and IL1, as well as their respective receptors, share no similarities in sequence and structure, it has long been speculatedthat these two cytokines might utilize similar intracellularsignaling mechanisms based on their overlapping biological activities. For the past few years, our laboratorieshave investigated the TNF and IL-1 signaling pathwaysthat lead to NF-κB activation. Using biochemical methods and genetic screens for interacting proteins, we haveunraveled several steps in these signaling cascades. Ourfindings indicate that these two cytokines utilize distinctreceptor-proximal signaling molecules but share a common downstream pathway. Furthermore, the role of someupstream molecules are not confined to IL-1 or TNF signal transduction but extend to other members of their respective receptor families...