Negatively-regulated necroptosis by autophagy required caspase-6 activation in TNFα-treated murine fibrosarcoma L929 cells.

Negatively-regulated necroptosis by autophagy required caspase-6 activation in TNFα-treated murine fibrosarcoma L929 cells. Int Immunopharmacol. 2013 Aug 10; Authors: Ye YC, Wang HJ, Chen L, Liu WW, Tashiro SI, Onodera S, Xia MY, Ikejima T Abstract Autophagy and necroptosis have been known to be interconnected, while the relationship between autophagy and necroptosis remains unclear. Here, we demonstrated that pan-caspase inhibitor z-VAD-fmk (zVAD) exacerbated TNFα-induced necroptosis and autophagy in murine fibrosarcoma L929 cells. And the RIP-1 inhibitor necrostatin-1 inhibited TNFα+zVAD-induced necroptosis and autophagy. Inhibition of autophagy by 3-methyladenine (3MA) or small interfering RNA (siRNA) against Beclin 1 augmented TNFα-induced necroptosis, while, autophagy inhibition did not influence TNFα+zVAD-induced necroptosis. These results suggested that autophagy was a downstream consequence of necroptosis, and had a negative-feedback function to necroptosis in TNFα-treated L929 cells, but not in the presence of zVAD. Subsequently, TNFα administration was accompanied with caspase-6 activation. Inhibition of caspase-6 activity by z-V-E(OMe)-I-D(OMe)-fmk (zVEID) or caspase-6 (p20) siRNA had no effect on necroptosis but promoted TNFα-induced autophagy. Meanwhile, autophagy inhibition further increased caspase-6 activation. Caspase-6 (p20) siRNA sequestered the increased necroptotic ratio by 3MA pretreatment in TNFα-treated L929 ce...
Source: International Immunopharmacology - Category: Allergy & Immunology Authors: Tags: Int Immunopharmacol Source Type: research