TNFsRI ELISA Kit, Human

In addition to TNFR1-induced activation of stress-induced kinase signaling in contributing to apoptotic signaling, TNFR1 can be internalized after TNF binding and this leads to dissociation of the TRADD/TRAF2/RIP complex and association of Fas-associated DD (FADD), recruitment of pro-caspase 8, and formation of the death-inducing signaling complex (DISC), triggering activation of the executioner caspases through the extrinsic apoptosis pathway. Caspase-8, combined with its ability to induce apoptosis through the extrinsic pathway, also triggers the intrinsic apoptosis pathway by cleaving the pro-apoptotic Bcl-2 family members Bax and Bid to initiate mitochondrial-induced apoptosis. The complexity of TNFR1-mediated signaling is what allows many divergent (ie, proliferation, activation, apoptosis) outcomes to occur as a result of TNF signaling.³

TNF actions may also be constrained in part by metalloprotease-dependent cleavage of membrane-bound TNF receptors, which can be triggered by a number of proinflammatory stimuli. Cleavage is thought to contribute to the clearance of TNFR1 and TNFR2 from the membrane, and produces a pool of soluble receptors that may attenuate the inflammatory response by competing with membrane-bound receptors.⁴ Mice homozygous for a targeted mutation in an enzyme that cleaves several membrane proteins (including TNF and TNFR2) have numerous developmental defects, emphasizing the physiologic importance of ectodomain shedding.