The TNF receptor superfamily (TNFRSF, provisional nomenclature) displays limited homology beyond an extracellular domain rich in cysteine residues and is activated by at least 18 different human homologues of TNF referred to as the TNF superfamily (TNFSF). Some homologues lacking transmembrane and cytoplasmic domains function as decoy receptors binding ligand without inducing cell signalling. Many of these receptors and ligands function as multimeric entities. Signalling through these receptors is complex and involves interaction with cytoplasmic adaptor proteins (such as TRADD and TRAF1). Several of these receptors contain cytoplasmic motifs known as ‘death domains’, which upon activation serve to recruit death domain- and death effector domain-containing proteins crucial for the initiation of an apoptotic response. Additional signalling pathways include the regulation of the nuclear factor κB or mitogen-activated protein kinase pathways. Pharmacological manipulation of these receptors is mainly enacted through chelating the endogenous agonists with humanised monoclonal antibodies (e.g. infliximab or adalimumab) or recombinant fusion proteins of IgG and soluble receptors (e.g. etanercept). Some mutated forms of TNF ligands are capable of selecting for different receptor subtypes.

TNFRSF1A is preferentially activated by the shed form of TNF ligand, whereas the membrane-bound form of TNF serves to activate TNFRSF1A and TNFRSF1B equally.

TNFRSF6B (ENSG00000243509, also known as the decoy receptor for Fas ligand (DcR3), TR6, M68) acts as a non-functional target for TNFSF14, TNFSF15 and TNFSF6. TNFRSF10C (ENSG00000173535, also known as decoy receptor 1, DcR1, decoy TRAIL receptor without death domain, TNF- related apoptosis-inducing ligand receptor 3, TRAIL-R3, LIT, TRID, CD263) and TNFRSF10D (ENSG00000173530, also known as decoy receptor 2, DcR2, TNF-related apoptosis-inducing ligand receptor 4, TRAIL-R4, TRUNDD, CD264) act as non-functional targets for TNFSF10.

The tumour necrosis factor ligand superfamily includes TNFSF1 (ENSG00000204496, TNFβ, lymphotoxin-α, LTα), TNFSF2 (ENSG00000204490, TNF, TNFα, cachectin, necrosin, cytotoxin, DIF), TNFSF3 (ENSG00000227507, TNFC, LTB, lymphotoxin-β, LTβ), TNFSF4 (ENSG00000117586, OX-40 ligand, CD252, glycoprotein Gp34, TAX transcriptionally-activated glycoprotein 1, TXGP-1), TNFSF5 (ENSG00000102245, CD40 ligand, CD154, gp39, TNF-related activation protein, TRAP), TNFSF6 (ENSG00000117560, Fas ligand, CD95L, CD178, ApoI L, Apoptosis antigen ligand), TNFSF7 (ENSG00000125726, CD70, CD27 ligand, Ki-24), TNFSF8 (ENSG00000106952, CD30 ligand, CD153), TNFSF9 (ENSG00000125657, 4-1BB ligand, CDw137L), TNFSF10 (ENSG00000121858, TRAIL, Apo-2 ligand (Apo-2L), TL2, CD253), TNFSF11 (ENSG00000120659, Receptor activator of nuclear factor κB ligand, RANKL, TNF-related activation-induced cytokine, TRANCE, osteoprotegerin ligand, OPGL, osteoclast differentiation factor, ODF, CD254 antigen), TNFSF12 (TNF-related weak inducer of apoptosis, TWEAK, Apo-3 ligand, Apo3L, CD255), TNFSF13 (ENSG00000161955, APRIL, TALL2, TRDL-1, ZTNF2, TNFSF13A, CD256), TNFSF13B (ENSG00000102524, zTNF4, THANK, TNF- and APOL-related leukocyte expressed ligand 1, TALL-1, B lymphocyte stimulator, BLyS, B cell-activating factor, BAFF, dendritic cell-derived TNF-like molecule, DTL, CD257 antigen), TNFSF14 (ENSG00000125735, LIGHT, LTg, TR2, Herpesvirus entry mediator-ligand, CD258), TNFSF15 (ENSG00000181634, TL1,TL1A,VEGI, vascular endothelial cell growth inhibitor, TNF ligand-related molecule 1), and TNFSF18 (ENSG00000120337, TL6, glucocorticoid- induced TNF-related ligand, activation-inducible TNF-related ligand).

Cretney, E; Takeda, K; Smyth, MJ. (2007) Cancer: novel therapeutic strategies that exploit the TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway. Int. J. Biochem. Cell Biol., 39 (2): 280-6. [PMID:17097329]

Croft, M. (2005) The evolving crosstalk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA. Trends Immunol., 26 (6): 292-4. [PMID:15922943]

Elewaut, D; Ware, CF. (2007) The unconventional role of LT alpha beta in T cell differentiation. Trends Immunol., 28 (4): 169-75. [PMID:17336158]

Paul, AT; Gohil, VM; Bhutani, KK. (2006) Modulating TNF-alpha signaling with natural products. Drug Discov. Today, 11 (15-16): 725-32. [PMID:16846800]

Popa, C; Netea, MG; van Riel, PL; van der Meer, JW; Stalenhoef, AF. (2007) The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. J. Lipid Res., 48 (4): 751-62. [PMID:17202130]

Scott, DL; Kingsley, GH. (2006) Tumor necrosis factor inhibitors for rheumatoid arthritis. N. Engl. J. Med., 355 (7): 704-12. [PMID:16914706]

Shen, HM; Pervaiz, S. (2006) TNF receptor superfamily-induced cell death: redox-dependent execution. FASEB J., 20 (10): 1589-98. [PMID:16873882]

Sriram, K; O'Callaghan, JP. (2007) Divergent roles for tumor necrosis factor-alpha in the brain. J Neuroimmune Pharmacol, 2 (2): 140-53. [PMID:18040839]

Tracey, D; Klareskog, L; Sasso, EH; Salfeld, JG; Tak, PP. (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol. Ther., 117 (2): 244-79. [PMID:18155297]

Wullaert, A; van Loo, G; Heyninck, K; Beyaert, R. (2007) Hepatic tumor necrosis factor signaling and nuclear factor-kappaB: effects on liver homeostasis and beyond. Endocr. Rev., 28 (4): 365-86. [PMID:17431229]