Cytokine Receptors (Tumor Necrosis Receptor Family)

The cytokines and receptors of the Tumor Necrosis Factor (TNF) superfamily serve as an intercellular communication network integrating cellular responses in vertebrates. TNF receptors activate signaling pathways for cell survival, death, and differentiation orchestrating the development, organization and homeostasis of lymphoid, mammary, neuronal and ectodermal tissues. Members of the TNF receptor superfamily (TNFRSF) may pair off with one or more specific ligands, which form a corresponding superfamily of ligands (TNFSF). Each ligand-receptor pair is considered a “system”, with more than 40 distinct recognized systems (see Table). The significant shared use of ligands or receptors observed in the different systems indicates the signaling pathways are highly integrative with unique functions derived in part from distinct signaling pathways activated by these cytokine systems. A standardized nomenclature for the TNF/TNFR superfamily was adopted aiding accessibility of the genomic databases, although the original acronyms remain in common use.

TNFR are type 1 membrane glycoproteins structurally defined by a cysteine-rich motif forming a molecule with an elongated extracellular domain containing the binding site for its specific ligand. The TNF related ligands are also membrane-anchored (type II) glycoproteins assembling into compact trimers that induce oligomerization of their specific receptors, which in turn activate signaling within the cell. From their membrane-anchored position, cell-to-cell contact is required to initiate signaling, except for those ligands that are shed from their membrane position diffusing to cellular receptors at distant sites. Soluble receptors formed by shedding and others that lack an encoded membrane domain function as decoys (antagonists). Some TNFR, like Fas, TRAIL-R1 and 2, and TNFR1 activate cell death by recruiting specific adaptor molecules, like FADD and caspase 8, which lead to apoptosis. Other TNFR, like the LTβR, CD40 and RANK activate transcription factors like NFkB and AP1 that regulate expression of genes protecting cells from apoptosis. Activating both cell death and survival pathways is the signaling paradox of this cytokine family.

TNF and Lymphotoxin-α (LTα), the prototypic members of the family, function in inflammatory and immune reactions through two shared receptors TNFR1 and TNFR2, having proinflammatory and anti-inflammatory effects. LTαβ-LTβR system is necessary for the genesis of secondary lymphoid organs as well as organizing microenvironments for lymphocytes during chronic inflammation. TNF’s role in inflammation leads to development of specific inhibitors fashioned from soluble TNFR (Enbrel™), which has proved highly effective in the treatment of autoimmune diseases such as rheumatoid arthritis. The related receptors Ox40, 41BB, HVEM, and CD27, for example, mediate signals involved in fine tuning T cell responses, promoting differentiation of effector and memory T cells. HVEM binds and regulates signaling through the inhibitory cosignaling regulator BTLA, an Ig superfamily member with an ITIM motif. The BAFF/APRIL and CD40 systems provide critical signals for antibody production by B lymphocytes. Thus, it is not surprising given the important roles played by members of the TNF superfamily in host defense that several different viral pathogens, including pox, herpes and retroviruses encode orthologs (virokines) that mimic or antagonize these cytokine systems.

The several other systems function as mediators of organ development and homeostasis. For example, EDA controls ectoderm and RANK controls bone homeostasis by regulating the differentiation of osteoblasts. Nerve growth factor receptor (p75) and Taj/TROY bind ligands unrelated to TNF, demarcating a major branch point in the TNFR family. Rather, NGFR and Taj bind neurotropins and Nogo-66 complex involved in regulating the regeneration of axons. The TNF homology domain (jellyroll β sandwich) is also observed in several proteins related to complement protein C1q. The diversification of the TNF superfamily into so many biological contexts reflects the versatility of the TNF and TNFR binding domains. As additional knowledge accumulates therapeutic manipulation of the TNF superfamily may have significant impact on human disease.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Standardized
Namea
TNFRSF1A TNFRSF1B TNFRSF3 TNFRSF4 TNFRSF5 TNFRSF6
Alternative
Names
CD18
p55TNFR
TNFRI
TNFRII
p75TNFR
LTβR OX40
CD134
CD40 Fas
APO-1
CD95
Chromosome
Position
12p13.2 1p36-p32 12p13 1p36 20q12-q13.2 10q24.1
Genbank
Accession No.b
NM_001065 NM_001066 NM_002342 NM_003327 NM_001250 NM_000043
Agonists/Ligandsc TNF (T0157T6674)
LTα (T7799)
TNF (T0157T6674)
LTα (T7799)
LIGHT
LT-αβ2 (L5162)
OX40L CD40L
FasL
Antagonists Enbrel™
Remicade™
Enbrel™
Remicade™
LTβR-Fc (L2885) Ox40-Fc Not Known
Fas-Fc (F8674)
DcR3-Fc (D2441)
Signal
Transduction
Mechanisms
TRAFs
SAPKs
NFκB
Caspases
TRAFs
SAPKs
NFκB
TRAFs
SAPKs
NFκB
TRAFs
SAPKs
NFκB
TRAFs
SAPKs
NFκB
SAPKs
NFκB
Caspases
Physiological
Function
Inflammation/Host defense Activated T cell population contraction Lymphoid organogenesis and homeostasis Enhances T cell activation and responses Ig class-switching; Germinal center formation Activated T cell population contraction
Disease
Relevance
Autoinflammatory diseases, Autoimmunity Susceptibility to bacterial infections, Autoimmunity Autoimmunity, Inflammatory bowel disease (IBD) Defective T cell recall responses Immunodeficiency Autoimmunity (like ALPSd)

 

Standardized
Namea
TNFRSF6B TNFRSF7 TNFRSF8  TNFRSF9 TNFRSF10A TNFRSF10B 
Alternative
Names
DcR3
M86
TR6
CD27
Tp55
CD30 4-1BB TRAILR1
Apo-2
DR4
TRAILR2
Trick2A
DR5
Chromosome
Position
20q13.3 12p13 1p36 1p36 8p21 8p22-p21
Genbank
Accession No.b
NM_003823 NM_001242 NM_001243 NM_001561 NM_003844 NM_003842
Agonists/Ligandsc FasL
TL1A
LIGHT
CD27L CD30L (C6112 (h), C6237 (m)) 4-1BBL TRAIL (T5694, T9701) TRAIL (T5694, T9701)
Antagonists Not Known
CD27-Fc Not Known
4-1BB-Fc Not Known
Not Known
Signal
Transduction
Mechanisms
No signal TRAFs
SAPKs
NFκB
TRAFs
SAPKs
NFkB
NFkB NFkB
Caspases
NFkB
Caspases
Physiological
Function
Soluble decoy receptor Germinal center formation Regulates memory
T cell responses
T cell costimulation  Lymphocyte and tumor cell apoptosis Lymphocyte and tumor cell apoptosis
Disease
Relevance
Tumor evasion Defective T cell responses, Autoimmunity Disease marker in Hodgkin’s disease, T cell lymphomas Graft-versus-host disease, Cancer immunotherapy Cancer immunotherapy Cancer immunotherapy

 

Standardized
Namea
TNFRSF10C  TNFRSF10D TNFRSF11A  TNFRSF11B TNFRSF12A TNFRSF13B
Alternative
Names
DcR1
TRAILR3
TRID
DcR2
TRAILR4
TRUNDD
RANK
TRANCE-R
OPG
OCIF
TR1
FN14
TWEAKR
TACI
Chromosome
Position
8p22-p21 8p21 18q22.1 8q24 16p13.3 17p11.2
Genbank
Accession No.b
NM_003841 NM_003840 NM_003839 NM_002546    
Agonists/Ligandsc TRAIL (T5694, T9701)
TRAIL (T5694, T9701)
RANKL (T3573) RANKL (T3573) TWEAK APRIL (A1354)
BAFF
Antagonists Not Known
Not Known
Not Known
Not Known
Not Known
TACI-Fc
Signal
Transduction
Mechanisms
No signal No signal TRAFs
NFkB
No signal NFkB TRAFs
Physiological
Function
Inhibits TRAIL Same as TNFRSF10C Bone homeostasis, Mammary gland and Peyer’s patch development Bone formation/ homeostasis Regulates cell survival/ apoptosis, angiogenesis
Enhances B cell survival
Disease
Relevance
Not Known Not Known
Osteoporosis Osteoporosis, Arterial calcification Skin disorders, CNS inflammation (like EAEe)
Autoimmunity

 

Standardized
Namea
TNFRSF13C TNFRSF14 TNFRSF16 TNFRSF17 TNFRSF18 TNFRSF19L
Alternative
Names
BAFFR HVEM, HveA, TR2
LIGHTR
ATAR
NGFR
p75NTR
BCMA AITR
GITR
TL6
RELT
Chromosome
Position
22q13.1-q13.31 1p36.3-p36.2 17q12-q22 16p13.1 1p36.3 11q13.2
Genbank
Accession No.b
           
Agonists/Ligandsc BAFF LIGHT
LTα (T7799)
BTLA
NGF (N1408)
BDNF (B3795)
APRIL (A1354)
BAFF
AITRL Not Known
Antagonists BAFFR-Fc (B4060)
HVEM-Fc (H9785)
Not Known
Not Known
Endokine™ Not Known
Signal
Transduction
Mechanisms
NFkB TRAFs Not Known
Not Known
Not Known
TRAFs
NFkB
Physiological
Function
Costimulates T cell proliferation, B cell survival
HSV entry receptor, T cell costimulation
Angiogenesis, cutaneous neuron development
Enhances B cell survival, Ig class switching
Inhibits T cell receptor-dependent apoptosis
Not Known
Disease
Relevance
Autoimmunity Autoimmunity Defective neuron innervation
Autoimmunity Autoimmunity Not Known

 

Standardized
Namea
TNFRSF19 TNFRSF21 TNFRSF25f EDAR XEDAR
Alternative
Names
TROY
TAJ
TRADE
DR6 WSL-1, TRAMP, AIR, APO-3, DDR3, DR3, LARD, TR3, WSLLR
ED1R
ED5
EDA3
EDA2R
Chromosome
Position
13q12.11-q12.3 6P12.2-21.1 1p36.3 2q11-q13 Xq11.1
Genbank
Accession No.b
         
Agonists/Ligandsc NgR1/LINGO1 Not Known
TL1A EDA1 EDA2
Antagonists Not Known
Not Known
Not Known
Not Known
Not Known
Signal
Transduction
Mechanisms
RhoA
c-Jun
NFkB
Caspases
NFkB
Caspases
NFkB
Caspases
TRAFs
Physiological
Function
Inhibits neurite outgrowth
Attenuates lymphoproliferation
Enhances NK cell and monocyte cytotoxicity
Hair/sweat gland formation and development
Hair/sweat gland formation and development
Disease
Relevance
Axonal regeneration
Not Known
Not Known
Hypohydrotic ectodermal dysplasia
Hypohydrotic ectodermal dysplasia

 

Footnotes

a) Standardized gene symbols were acquired from: http://www.gene.ucl.ac.uk/nomenclature/; includes further details, such as linked human genomic and tissue expression databases, etc.

b) All accession numbers are for human mRNA.

c) Product numbers refer to human proteins. For further species, visit our website at www.sigma-aldrich.com and use our Product Search.

d) Autoimmune lymphoproliferative syndrome is typified by defective lymphocyte apoptosis; usually leads to autoimmunity.

e) Experimental autoimmune encephalomyelitis

f) Previously TNFRSF12; a TNFRSF12L (or DR3L) has been characterized as a duplicate of the DR3 gene, and implicated in rheumatoid arthritis.

 

Abbreviations

AIR: Apoptosis-inducing receptor
AITR: Activation-inducible TNF-related member
AP1: Activator protein 1
APO: Apoptosis antigen
APRIL: A proliferation-inducing ligand
ATAR: Another TRAF-associated receptor
BAFF: B cell-activating factor
BCMA: B cell maturation antigen
BDNF: Brain-derived neurotrophic factor
BTLA: B and T lymphocyte attenuator
DcR: Decoy receptor
DDR3: death-domain-containing receptor
DR: Death receptor
EDA: Ectodysplasin-A
FADD: FAS-associated death domain-containing protein
GITR: Glucocorticoid-induced TNF-related member
HVEM: Herpes virus entry mediator
ITIM: immunoreceptor tyrosine-based inhibitory motif
LARD: Lymphocyte-associated receptor of death
LIGHT: Lymphotoxin-like, exhibits inducible expression, and competes with HSV glycoprotein D (gD) for HVEM, a receptor expressed by T cells
LT: Lymphotoxin
NFκB: Nuclear factor kappa B
NGF: Nerve growth factor
NgR1: Nogo-66 receptor 1
OCIF: Osteoclastogenesis inhibitory factor
OPG: Osteoprotegerin
RANK: Receptor activator of NFκB
RELT: Receptor expressed in lymphoid tissues
SAPK: Stress-activated protein kinases
TACI: Transmembrane activator and CAML interactor
Taj: Toxicity and JNK inducer
TL: TNF-like
TNF: Tumor necrosis factor
TNFR: Tumor necrosis factor receptor
TNFSF: Tumor necrosis factor superfamily
TNFRSF: Tumor necrosis factor receptor superfamily
TR: TNF receptor-like
TRAF: TNF receptor-associated factor
TRAIL: Tumor necrosis factor related apoptosis inducing ligand
TRAMP: TNF-receptor-related apoptosis-mediated protein
TRANCE: TNF-related activation-induced cytokine
TROY: TNFRSF expressed on the mouse embryo
Trick: TRAIL receptor inducer of cell killing
TRID: TRAIL receptor without an intracellular domain
TRUNDD: TRAIL receptor with a truncated death domain
TWEAK: TNF-like weak inducer of apoptosis
XEDAR: X-linked ectodysplasin-A2 receptor

 

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References