炎症细胞因子肿瘤坏死因子α（TNF-α）以免疫和非约束细胞类型表达，包括巨噬细胞，T细胞，肥大细胞，粒细胞，天然杀伤（NK）细胞，成纤维细胞，神经元，角质形成细胞和平滑肌细胞作为反应对组织损伤或免疫应答对致病刺激（KöckA.等人1990; Dubravec DB等人1990; Walsh LJ等人1991; Te Velde Aa等，1990; imaizumi t等人。2000）。TNF-α用两个受体相互作用，即TNF受体1（TNFR1）和TNF受体2（TNFR2）。TNFR1的激活可以触发多个信号转导途径诱导炎症，增殖，存活或细胞死亡（Ward C等人1999; Micheau O和Tschopp J 2003; Wiersa D等人2006）。TNF-α-刺激的细胞是否会存活或死亡取决于自分泌/旁碱信号，以及在细胞上下文上。
TNF与TNFR1结合最初导致复合物I的形成，该复合物I由TNFR1、TRADD (TNFR1相关死亡域)、TRAF2 (TNF受体相关因子-2)、RIPK1(受体相互作用丝氨酸/苏氨酸蛋白激酶1)、E3泛素连接酶BIRC2,BIRC3 (cIAP1/2，细胞凋亡抑制剂)和LUBAC (Micheau O and Tschopp J 2003)。泛素链通过BIRC2/3和LUBAC(由HOIP、HOIL-1和SHARPIN组成)与RIPK1结合，可以进一步募集和激活TAK1(也称为有丝裂原活化蛋白激酶激酶激酶7 (MAP3K7))复合物和IκB激酶(IKK)复合物。TAK1和IKK使RIPK1磷酸化，以限制其细胞毒活性，并激活激活B细胞核因子κ轻链增强子(NFkappaB)和丝裂原激活蛋白(MAP)激酶信号通路，通过诱导抗凋亡蛋白(如BIRC)促进细胞存活。细胞FLICE (fadd样il -1β-转换酶)样抑制蛋白(cFLIP)和促炎细胞因子(TNF和IL-6)的分泌。当生存途径被抑制时，TRADD:TRAF2:RIPK1从膜结合的TNFR1信号复合物中分离，并招募fas相关死亡结构域含蛋白(FADD)和procaspase-8(也称为复合物II)。一旦招募到FADD，多个procaspase-8分子通过它们的串联死亡效应结构域(DED)相互作用。从而促进procaspase-8的近缘诱导二聚和蛋白水解，这是启动凋亡细胞死亡所必需的(Hughes MA et al. 2009;Oberst A et al. 2010)。当半胱天冬酶活性抑制某些病理生理条件下(例如caspase-8抑制蛋白质如CrmA和vICA后感染牛痘病毒或巨细胞病毒)或药理代理人,deubiquitinated RIPK1在物理上和功能上的相同器官RIPK3导致necrosome的形成,由RIPK1和RIPK3组成的坏死诱导复合物(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). Within the complex II procaspase-8 can also form heterodimers with cFLIP isoforms, FLIP long (L) and FLIP short (S), which are encoded by the NFkappaB target gene CFLAR (Irmler M et al. 1997; Boatright KM et al. 2004; Yu JW et al. 2009; Pop C et al. 2011). FLIP(S) appears to act purely as an antagonist of caspase-8 activity blocking apoptotic but promoting necroptotic cell death (Feoktistova et al. 2011). The regulatory function of FLIP(L) has been found to differ depending on its expression levels. FLIP(L) was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP(L) enhanced DR signaling to apoptosis (Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011; Yu JW et al. 2009; Hughes MA et al. 2016). In addition, caspase-8:FLIP(L) heterodimer activity within the TRADD:TRAF2:RIPK1:FADD:CASP8:FLIP(L) complex allowed cleavage of RIPK1 to cause the dissociation of the TRADD:TRAF2:RIP1:FADD:CASP8, thereby inhibiting RIPK1-mediated necroptosis (Feoktistova et al. 2011, 2012). 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/necroptotic pathway, and the other NFkappaB, and MAPK pathways providing highly specific cell responses initiated by various types of stimuli.
