Bcl-xL suppresses TNF-mediated apoptosis and activation of nuclear factor-κB, activation protein-1, and c-Jun N-terminal kinase

Tumor necrosis factor (TNF) is a multipotential cytokine that induces apoptosis and activates nuclear factor-kappa B (NF-kappa B), activation protein 1 (AP-1), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK), Several mechanisms have been suggested to explain these effects of TNF, one of them being the involvement of reactive oxygen intermediates (ROI), Because Bcl-2 family members are known to affect the redox status of the cell, we examined the effect of Bcl-x(L) expression on TNF signaling. Overexpression of BcI-x(L) in human promyelocytic lymphoma HL-60 cells downregulated TNF-induced cytotoxicity, Cleavage of poly (ADP-ribose) polymerase by caspases, an early indicator of apoptosis, was also blocked by Bcl-x(L) overexpression, Activation of NF-kappa B was significantly suppressed in cells overexpressing Bcl-x(L), as was degradation of I kappa B alpha, the inhibitory subunit of NF-kappa B, NF-kappa B activation induced by serum-activated lipopolysaccharide (SALPS), ceramide, and okadaic acid was also inhibited by overexpression of Bcl-x(L), whereas that by phorbol myristate acetate (PMA) and H2O2 was unaffected. Besides NF-kappa B, the activation of AP-1 by TNF also was blocked by Bcl-x(L). The activation of JNK and MAPK kinase, which regulate these transcription factors, was reduced in Bcl-x(L)-transfected cells. Overall, our results demonstrate that Bcl-x(L) inhibits TNF signaling at an early step common to induction of activation of apoptosis, NF-kappa B, AP-1, MAPK, and JNK.