肿瘤坏死因子受体1 (TNFR1)的激活可以触发多种信号转导通路，诱导炎症、细胞增殖、存活或细胞死亡(Ward C et al. 1999;陈志强，陈志强，陈志强，2003;Widera D et al. 2006)。肿瘤坏死因子刺激的细胞是否存活或死亡取决于细胞环境。tnf - α诱导的信号导致转录因子的激活，如核因子-kappa B (NFkappaB)和激活蛋白-1 (AP1) (Ward C et al. 1999;Widera D et al. 2006;祖香港等人2012)。
tnf - α与TNFR1的结合导致了适配器蛋白TNFR1相关死亡域(TRADD)和受体相互作用蛋白1 (RIPK1)的募集。TRADD随后也招募TNF受体相关因子2 (TRAF2)。RIPK1迅速被k63 -泛素化，导致TAB2:TAK1复合物和IkB激酶(IKK)复合物向TNFR1募集。激活的IKK复合物介导NFkappaB抑制剂(IkB)的磷酸化，以IkB为靶点进行泛素化和随后的降解。释放的NFkappaB诱导多种基因的表达，包括炎症相关基因和抗凋亡基因编码的蛋白，如凋亡抑制蛋白cIAP1/2、Bcl-2、Bcl-xL或细胞fly样抑制蛋白(FLIP) (Blonska M et al. 2005;Ea CK等人2006;Wu CJ et al. 2006;Chen C et al. 2000;Manna SK等人2000年;Kreuz S et al. 2001; Micheau O et al. 2001). NFkB-mediated inhibition of cell death also involves attenuating TNF-induced activation of c-Jun activating kinase (JNK). Whereas transient activation of JNK upon TNF treatment is associated with cellular survival, prolonged JNK activation contributes to cell death. However, as caspases activate JNK quite efficiently, JNKs are also regularly stimulated in course of apoptosis without being essential for cell death (Wicovsky A et al. 2007). AP1-mediated gene induction results from activation of JNK via TRAF2 (not shown here) (Tsou HK et al. 2012). While pro-survival signaling is initiated and regulated via the activated TNFR1 receptor complex at the cell membrane, cell death signals are induced by internalization-associated fashion upon the release of RIPK1 from the membrane complex (Micheau O and Tschopp J 2003; Schneider-Brachert W et al. 2004; Tchikov V et al. 2011).
tnfr1介导的NFkB转录活性既抗凋亡又高度促炎，因此必须严格调控，以防止结构性激活导致持续性炎症和癌症(Ward C et al. 1999;Fujihara S et al. 2002;Pekalski J et al. 2013;Kankaanranta H et al. 2014;Shukla S和Gupta S 2004;Jackson-Bernitsas DG et al. 2007;张建宇等。2007)。通常有多种机制确保对NFkappaB激活的适当控制，包括由NFkappaB诱导抑制剂ikb - α (NFKBIA)和泛素编辑蛋白A20介导的两个负反馈循环(He KL & Ting AT 2002;Wertz IE et al. 2004;Vereecke L et al. 2009; Pekalski J et al. 2013).
