Tumor necrosis factor alpha (TNF
α) has been reported to induce necroptosis and autophagy, but its mechanisms remain unclear. In this study, we found that TNF
α significantly induced necroptosis and autophagy in murine fibrosarcoma L929 cells. The necroptosis inhibitor necrostatin-1 (Nec-1) completely blocked TNF
α-induced necroptosis and autophagy, but inhibition of autophagy with 3-methyladenine (3MA) or Beclin 1 small interfering RNA (siRNA) promoted necroptosis, indicating that autophagy acted as a negative regulator of TNF
α-induced necroptosis. The cytotoxicity of TNF
α was accompanied by decreased expressions of phosphorylated p38 mitogen-activated protein kinase (p-p38) and nuclear factor-kappa B (NF-
κB), and inhibition of p38 and NF-
κB activation by chemical inhibitors or siRNA augmented these necroptotic and autophagic responses to TNF
α in the cells. The pan-caspase inhibitor z-VAD-fmk (zVAD) exacerbated TNF
α-induced necroptosis and autophagy. Combined treatment with TNF
α and zVAD further decreased the expressions of p-p38 and NF-
κB compared with TNF
α alone treatment. Consequently, these results indicated that suppression of the p38–NF-
κB survivial signaling pathway promoted necroptotic and autophagic cell death in TNF
α-treated L929 cells.
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