The inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is expressed in immune and nonimmune cell types including macrophages, T cells, mast cells, granulocytes, natural killer (NK) cells, fibroblasts, neurons, keratinocytes and smooth muscle cells as a response to tissue injury or upon immune responses to pathogenic stimuli (Köck A. et al. 1990; Dubravec DB et al. 1990; Walsh LJ et al. 1991; te Velde AA et al. 1990; Imaizumi T et al. 2000). TNF-alpha interacts with two receptors, namely TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Activation of TNFR1 can trigger multiple signal transduction pathways inducing inflammation, proliferation, survival or cell death (Ward C et al. 1999; Micheau O and Tschopp J 2003; Widera D et al. 2006). Whether a TNF-alpha-stimulated cell will survive or die is dependent on autocrine/paracrine signals, and on the cellular context.
TNF binding to TNFR1 results initially in the formation of Complex I that consists of TNFR1, TRADD (TNFR1-associated death domain), TRAF2 (TNF receptor associated factor-2), RIPK1 (receptor interacting protein kinase 1), and BIRC1 and BIRC3 (cIAP1/2,cellular inhibitor of apoptosis) (Micheau O and Tschopp J 2003). This complex by default activates NFkappaB promoting cell survival (induction of anti-apoptotic proteins such as BIRC, cFLIP) and secretion of pro-inflammatory cytokines (TNF and IL-6). When the survival pathway is inhibited, TNF-induced signaling leads to the formation of Complex II that is made up of TRADD, FADD (Fas-associated death domain-containing protein, RIPK1,and procaspase-8 leading to the activation of caspase-8 and apoptotic cell death. When caspase activity is inhibited under certain pathophysiological conditions (e.g. caspase-8 inhibitory proteins such as CrmA and vICA after infection with cowpox virus or CMV) or by pharmacological agents, deubiquitinated RIPK1 is physically and functionally engaged by its homolog RIPK3 leading to formation of the necrosome, a necroptosis-inducing complex consisting of RIPK1 and RIPK3 (Tewari M & Dixit VM 1995; Fliss PM & Brune W 2012; Sawai H 2013; Moquin DM et al. 2013; Kalai M et al. 2002; Cho YS et al. 2009, He S et al. 2009, Zhang DW et al., 2009).TNF-alpha can also activate sphingomyelinase (SMASE, such as SMPD2,3) proteins to catalyze hydrolysis of sphingomyeline into ceramide (Adam D et al.1996; Adam-Klages S et al. 1998; Ségui B et al. 2001). Activation of neutral SMPD2,3 leads to an accumulation of ceramide at the cell surface and has proinflammatory effects. However, TNF can also activate the pro-apoptotic acidic SMASE via caspase-8 mediated activation of caspase-7 which in turn proteolytically cleaves and activates the 72kDa pro-A-SMase form (Edelmann B et al. 2011). Ceramide induces anti-proliferative and pro-apoptotic responses. Further, ceramide can be converted by ceramidase into sphingosine, which in turn is phosphorylated by sphingosine kinase into sphingosine-1-phosphate (S1P). S1P exerts the opposite biological effects to ceramide by activating cytoprotective signaling to promote cell growth counteracting the apoptotic stimuli (Cuvillier O et al. 1996). Thus, TNF-alpha-induced TNFR1 activation leads to divergent intracellular signaling networks with extensive cross-talk between the pro-apoptotic pathway, and the other NFkappaB, and JNK pathways providing highly specific cell responses initiated by various types of stimuli.