A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50 000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed. Cell Death and Differentiation (2003) 10, 45–65. doi:10.1038/ sj.cdd.4401189

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Tumor necrosis factor signaling.

Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis. Apoptosis is dependent on caspase activation, whereas the caspase-independent necrotic signaling pathway remains largely uncharacterized. We show here that Fas kills activated primary T cells efficiently in the absence of active caspases, which results in necrotic morphological changes and late mitochondrial damage but no cytochrome c release. This Fas ligand-induced caspase-independent death is absent in T cells that are deficient in either Fas-associated death domain (FADD) or receptor-interacting protein (RIP). RIP is also required for necrotic death induced by tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). In contrast to its role in nuclear factor kappa B activation, RIP requires its own kinase activity for death signaling. Thus, Fas, TRAIL and TNF receptors can initiate cell death by two alternative pathways, one relying on caspase-8 and the other dependent on the kinase RIP.

Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule.

Apoptosis in the immune system is a fundamental process regulating lymphocyte maturation, receptor repertoire selection and homeostasis Thus, death by apoptosis is as essential for the function of lymphocytes as growth and differentiation This article focuses on death receptor-associated apoptosis and the role of CD95 (Apo-1/Fas)-mediated signalling in T-cell and B-cell development and during the course of an immune response Gaining an insight into these processes improves our understanding of the pathogenesis of diseases such as cancer, autoimmunity and AIDS, and opens new approaches to rational treatment strategies

CD95's deadly mission in the immune system

Cancer cells often develop resistance to chemotherapy or irradiation through mutations in the p53 tumour-suppressor gene, which prevent apoptosis induction in response to cellular damage. Death receptors — members of the tumour-necrosis factor receptor (TNFR) superfamily — signal apoptosis independently of p53. Decoy receptors, by contrast, are a non-signalling subset of the TNFR superfamily that attenuate death-receptor function. Agents that are designed to activate death receptors (or block decoy receptors) might therefore be used to kill tumour cells that are resistant to conventional cancer therapies.

Targeting death and decoy receptors of the tumour-necrosis factor superfamily

Virtually all of the measurable cell-mediated cytotoxicity delivered by cytotoxic T lymphocytes and natural killer cells comes from either the granule exocytosis pathway or the Fas pathway. The granule exocytosis pathway utilizes perforin to traffic the granzymes to appropriate locations in target cells, where they cleave critical substrates that initiate DNA fragmentation and apoptosis; granzymes A and B induce death via alternate, nonoverlapping pathways. The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances. The interplay between these two cytotoxic systems provides opportunities for therapeutic interventions to control autoimmune diseases and graft vs. host disease, but oversuppression of these pathways may also lead to increased viral susceptibility and/or decreased tumor cell killing.

Lymphocyte-Mediated Cytotoxicity

ertain cytokines of the tumour-necrosis factor (TNF) family and their cognate receptors (collectively named death receptors) are potent inducers of programmed cell death (apoptosis). One such protein is the cell-surface receptor Fas, which, upon ligand binding, trimerizes and recruits the adaptor protein FADD through the cytoplasmic death domain of Fas. FADD then binds and activates procaspase-8 (ref. 1). TRAIL, the most recently identified member of the TNF family of death ligands, can induce apoptosis in a wide variety of tumour cells but not in normal cells. TRAIL induces apoptosis through two death-domain-containing receptors, TRAIL-R1 (also called death receptor (DR) 4) and TRAIL-R2 (or DR5). Investigation of the intracellular signalling pathways responsible for TRAIL-receptor-induced apoptosis has produced controversial results. Genetic evidence indicates the C

Joe Blenis

Papers

TRAIL receptor-2 signals apoptosis through FADD and caspase-8