Intracellular signals and events activated by cytokines of the tumor necrosis factor superfamily: From simple paradigms to complex mechanisms.

Tumor necrosis factor (TNF) and several related cytokines can induce opposite effects such as cell activation and proliferation or cell death. How the cell maintains the balance between these seemingly mutually exclusive pathways has long remained a mystery. TNF receptor I (TNFRI) initially emerged as a potent activator of NFkappaB and AP-1 transcription factors, while the related CD95 (Fas, Apo-1) was recognized as a prototype death receptor. Advances in research have uncovered critical molecular players in these intracellular processes. They have also revealed a much more complex picture than originally thought. Several new signaling pathways, including the alternative NFkappaB activation cascade, have been uncovered, and previously unknown modes of cross-talk between intracellular signaling molecules were revealed. It also turned out that signaling mechanisms mediated by the TNF receptor superfamily members can operate not only in the immune system but also in organ development.