The members of the TNF ligand family exert their biological functions via interaction with their cognate membrane receptors, comprising the TNF receptor (TNF-R) family. The members of the TNF-R family contain one to six cysteine-rich repeats in their extracellular domain, typically each with three cysteine bridges. Two receptors, TNF-R1 (TNF receptor type 1; CD120a) and TNF-R2 (TNF receptor type 2; CD120b) bind membrane-integrated TNF (memTNF) as well as soluble TNF (sTNF), but also the secreted homotrimeric molecule lymphotoxin-α (LTα). TNF-R1 is constitutively expressed in most tissues, whereas expression of TNF-R2 is highly regulated and is typically found in cells of the immune system. In the vast majority of cells, TNF-R1 appears to be the key mediator of TNF signalling, whereas in the lymphoid system TNF-R2 seems to play a major role. The cytokine TNF, produced by macrophages/monocytes during acute inflammation may be considered to represent a major proinflammatory mediator, with an optional capacity to induce necrosis and apoptosis. In (patho)physiological situations, TNF shows a remarkable functional duality, being strongly engaged both in tissue regeneration/expansion and destruction.
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