Cell death checkpoints in the TNF pathway.

Tumor necrosis factor (TNF) plays a central role in orchestrating mammalian inflammatory responses. It promotes inflammation either directly by inducing inflammatory gene expression or indirectly by triggering cell death. TNF-mediated cell death-driven inflammation can be beneficial during infection by providing cell-extrinsic signals that help to mount proper immune responses. Uncontrolled cell death caused by TNF is instead highly detrimental and is believed to cause several human autoimmune diseases. Death is not the default response to TNF sensing. Molecular brakes, or cell death checkpoints, actively repress TNF cytotoxicity to protect the organism from its detrimental consequences. These checkpoints therefore constitute essential safeguards against inflammatory diseases. Recent advances in the field have revealed the existence of several new and unexpected brakes against TNF cytotoxicity and pathogenicity.