Tumor necrosis factor-mediated cell death: to break or to burst, that's the question

Abstract

In this review, we discuss the signal-transduction pathways of three major cellular responses induced by tumor necrosis factor (TNF): cell survival through NF-kappaB activation, apoptosis, and necrosis. Recruitment and activation of caspases plays a crucial role in the initiation and execution of TNF-induced apoptosis. However, experimental inhibition of caspases reveals an alternative cell death pathway, namely necrosis, also called necroptosis, suggesting that caspases actively suppress the latter outcome. TNF-induced necrotic cell death crucially depends on the kinase activity of receptor interacting protein serine-threonine kinase 1 (RIP1) and RIP3. It was recently demonstrated that ubiquitination of RIP1 determines whether it will function as a pro-survival or pro-cell death molecule. Deeper insight into the mechanisms that control the molecular switches between cell survival and cell death will help us to understand why TNF can exert so many different biological functions in the etiology and pathogenesis of human diseases.

Fig. 1

NF-κB activation and apoptosis induced by TNF-R1 activation. Engagement of TNF-R1 activates a pathway that induces NF-κB activation through ubiquitinated RIP1. The NF-κB gene products counteract apoptosis at different levels and induce inflammatory responses. TRADD/FADD/RIP1 associations lead to activation of caspase-8 and apoptosis through a pathway that either is or is not cFLIP-sensitive. The cFLIP-insensitive pathway requires the kinase activity of RIP1 to form FADD/RIP1/caspase-8 complexes, and RIP1 must not be ubiquitinated. Caspase-8 mediated tBID/BAX translocation to the outer membrane of mitochondria induces MOMP with release of cyt C and SMAC. Cytochrome c, together with (d)ATP allows rearrangements of APAF-1, leading to recruitment and activation of caspase-9 and apoptosis. Release of SMAC creates a permissive condition for caspase activation. Some SMAC mimetics inhibit XIAP activity. See text for details

Fig. 2

Necrotic cell death is the result of interplay between several signaling cascades. Kinase activity of RIP1 is needed to induce necrosis in several in vitro and in vivo models. The main players in the propagation of necrosis are RIP3, calcium and mitochondria. RIP3 interacts with RIP1 and binds to several enzymes of the carbohydrate and glutamine metabolism. Calcium controls activation of PLA₂, calpains and NOS, which induce a series of events leading to necrotic cell death. Mitochondria contribute to necrosis by excessive ROS formation, mPT, and ATP depletion due to mitochondrial dysfunction. Several of these mediators are implicated in a self-amplifying loop. See text for details