2. Signaling Pathways
  3. Apoptosis
  4. TNF Receptor

TNF Receptor

Tumor Necrosis Factor Receptor; TNFR

TNF Receptor

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Tumor necrosis factor (TNF) is a major mediator of apoptosis as well as inflammation and immunity, and it has been implicated in the pathogenesis of a wide spectrum of human diseases, including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases.

TNF-α is a 17-kDa protein consisting of 157 amino acids that is a homotrimer in solution. In humans, the gene is mapped to chromosome 6. Its bioactivity is mainly regulated by soluble TNF-α–binding receptors. TNF-α is mainly produced by activated macrophages, T lymphocytes, and natural killer cells. Lower expression is known for a variety of other cells, including fibroblasts, smooth muscle cells, and tumor cells. In cells, TNF-α is synthesized as pro-TNF (26 kDa), which is membrane-bound and is released upon cleavage of its pro domain by TNF-converting enzyme (TACE).

Many of the TNF-induced cellular responses are mediated by either one of the two TNF receptors, TNF-R1 and TNF-R2, both of which belong to the TNF receptor super-family. In response to TNF treatment, the transcription factor NF-κB and MAP kinases, including ERK, p38 and JNK, are activated in most types of cells and, in some cases, apoptosis or necrosis could also be induced. However, induction of apoptosis or necrosis is mainly achieved through TNFR1, which is also known as a death receptor. Activation of the NF-κB and MAPKs plays an important role in the induction of many cytokines and immune-regulatory proteins and is pivotal for many inflammatory responses.

TNF Receptor Isoform Specific Products:

TNF Receptor Isoform Comparison
Cat. No. Product Name Effect Purity Chemical Structure
  • HY-P990040
    Exlinkibart
    		Inhibitor
    Exlinkibart (LVGN-6051) targets TNFRSF9 and is an IgG1κ antibody humanized through complementarity-determining region (CDR) grafting technology.
    Exlinkibart
  • HY-P99914
    Emfizatamab
    Emfizatamab is an anti-CD19/CD3E/TNFRSF9/PD-L1 monoclonal antibody.
    Emfizatamab
  • HY-P990757
    Ragistomig
    Ragistomig is an anti-TNFRSF9/CD274 IgG1 monoclonal antibody composed of a κ light chain and a variable region with a λ light chain and an IgG1 heavy chain. The overall structure is a dimer composed of two identical IgG1 heavy chains.
    Ragistomig
  • HY-B0809A
    Theophylline monohydrate
    		Inhibitor
    Theophylline (1,3-Dimethylxanthine) monohydrate is a potent phosphodiesterase (PDE) inhibitor, adenosine receptor antagonist, and histone deacetylase (HDAC) activator. Theophylline (1,3-Dimethylxanthine) monohydrate inhibits PDE3 activity to relax airway smooth muscle. Theophylline (1,3-Dimethylxanthine) monohydrate has anti-inflammatory activity by increase IL-10 and inhibit NF-κB into the nucleus. Theophylline (1,3-Dimethylxanthine) monohydrate induces apoptosis. Theophylline (1,3-Dimethylxanthine) monohydrate can be used for asthma and chronic obstructive pulmonary disease (COPD) research.
    Theophylline monohydrate
  • HY-P99470
    Benufutamab
    		Agonist 98.62%
    Benufutamab (GEN1029) is a death receptor 5 (DR5)-specific agonistic antibody. Benufutamab is a mixture of 2 noncompeting DR5-specific IgG1 antibodies, each with an E430G mutation in the Fc domain. Benufutamab has antitumor effects.
    Benufutamab
  • HY-P99782
    Opinercept
    		Inhibitor
    Opinercept is a tumor necrosis factor-alpha (TNF-alpha) inhibitor. Opinercept can be used for the research of rheumatoid arthritis (RA).
    Opinercept
  • HY-P99578
    Tanfanercept
    		Inhibitor
    Tanfanercept (HL036337) is an anti-TNF-α monoclonal antibody. Tanfanercept is effective in ameliorating corneal erosions in a dry eye (DE) mouse model.
    Tanfanercept
  • HY-P99704
    Licaminlimab
    		Inhibitor
    Licaminlimab (OCS-02) is a single-chain anti-TNF alpha antibody fragment. TNF alpha is an inflammatory cytokine produced by macrophages and monocytes during inflammation.
    Licaminlimab
  • HY-P99565
    Tengonermin
    		Inhibitor
    Tengonermin (ARENEGYR) is a vascular-targeting agent consisting of the human Tumour Necrosis Factor-α (TNF-α) conjugated with the CNGRCG peptide. Tengonermin increases penetration of intratumoral chemotherapy and T-cell infiltration by modifying the tumour microenvironment.
    Tengonermin
  • HY-160437
    TNF-α-IN-16
    		Inhibitor
    TNF-α-IN-16 is a potent TNFα inhibitor with an IC50 of <0.6 μM. TNF-α-IN-16 has antiinflammatory properties (WO2001072735A2; example 18).
    TNF-α-IN-16
  • HY-N5054
    (R)-5,7-Dimethoxyflavanone
    		Inhibitor ≥99.0%
    (R)-5,7-Dimethoxyflavanone shows potent antimutagenic activity against MeIQ mutagenesis in Ames test using the S. typhimurium TA100 and TA98 strains. And (R)-5,7-Dimethoxyflavanone significantly and dose-dependently inhibits the inflammatory mediato.
    (R)-5,7-Dimethoxyflavanone
  • HY-N0136R
    Taxifolin (Standard)
    Taxifolin (Standard) is the analytical standard of Taxifolin. This product is intended for research and analytical applications. Taxifolin ((+)-Dihydroquercetin) exhibits important anti-tyrosinase activity. Taxifolin exhibits significant inhibitory activity against collagenase with an IC50 value of 193.3 μM. Taxifolin is an important natural compound with antifibrotic activity. Taxifolin is a free radical scavenger with antioxidant capacity.
    Taxifolin (Standard)
  • HY-P990742
    Givastomig
    Givastomig is an anti-TNFRSF9/CLDN18 monoclonal antibody.
    Givastomig
  • HY-N0724R
    Mesaconitine (Standard)
    		Inhibitor
    Mesaconitine (Standard) is the analytical standard of Mesaconitine. This product is intended for research and analytical applications.
    Mesaconitine (Standard)
  • HY-N8884
    Coelonin
    		Inhibitor
    Coelonin is a dihydrophenanthrene with anti-inflammation activity. Coelonin inhibits LPS-induced PTEN phosphorylation. Coelonin inhibits NF-κB activation and p27Kip1 degradation by regulating the PI3K/AKT pathway negatively. Coelonin can inhibit IκBα phosphorylation and degradation and increases the expression of IκBα protein.
    Coelonin
  • HY-N6927R
    Isoforskolin (Standard)
    		Inhibitor
    Isoforskolin (Standard) is the analytical standard of Isoforskolin. This product is intended for research and analytical applications. Isoforskolin is the principle active component of C. forskohlii native to China. Isoforskolin reduces the secretion of lipopolysaccharide (LPS)-induced cytokines, namely TNF-α, IL-1β, IL-6 and IL-8, in human mononuclear leukocytes. Isoforskolin acts as an anti-inflammatory agent for the treatment of Lyme arthritis.
    Isoforskolin (Standard)
  • HY-161833
    HSP90-IN-31
    		Inhibitor
    HSP90-IN-31 (compound Be01) causes reduction of CD80 and CD86 expression on dendritic cells (DCs). HSP90-IN-31 decreases the production of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in BMDC and peritoneal macrophages stimulated by LPS (HY-D1056). Under the delayed-type hypersensitivity (DTH) mice model, HSP90-IN-31 reduces ear swelling and pro-inflammatory cytokines in the spleen.
    HSP90-IN-31
  • HY-N0042R
    Ginsenoside Rc (Standard)
    		Inhibitor
    Ginsenoside Rc (Standard) is the analytical standard of Ginsenoside Rc. This product is intended for research and analytical applications. Ginsenoside Rc, one of major Ginsenosides from Panax ginseng, enhances GABA receptorA (GABAA)-mediated ion channel currents (IGABA). Ginsenoside Rc inhibits the expression of TNF-α and IL-1β.
    Ginsenoside Rc (Standard)
  • HY-N0262R
    Cordycepin (Standard)
    Cordycepin (Standard) is the analytical standard of Cordycepin. This product is intended for research and analytical applications. Cordycepin (3'-Deoxyadenosine) is a nucleoside derivative and inhibits IL-1β-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts (RASFs) in a dose-dependent manner. Cordycepin kills Mycobacterium tuberculosis through hijacking the bacterial adenosine kinase.
    Cordycepin (Standard)
  • HY-115351
    GW-3333
    		Inhibitor
    GW-3333 is a potent and orally active TNF-alpha-converting enzyme (TACE) and matrix metalloproteinases (MMP) inhibitor. GW-3333 inhibits tumor necrosis factor-alpha (TNF-alpha) production. GW-3333 can be used in research of arthritis.
    GW-3333
Cat. No. Product Name / Synonyms Species Source
Cat. No. Product Name / Synonyms Application Reactivity
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Download TNF Receptor Signaling Pathway Map.

Following the binding of TNF to TNF receptors, TNFR1 binds to TRADD, which recruits RIPK1, TRAF2/5 and cIAP1/2 to form TNFR1 signaling complex I; TNFR2 binds to TRAF1/2 directly to recruit cIAP1/2. Both cIAP1 and cIAP2 are E3 ubiquitin ligases that add K63 linked polyubiquitin chains to RIPK1 and other components of the signaling complex. The ubiquitin ligase activity of the cIAPs is needed to recruit the LUBAC, which adds M1 linked linear polyubiquitin chains to RIPK1. K63 polyubiquitylated RIPK1 recruits TAB2, TAB3 and TAK1, which activate signaling mediated by JNK and p38, as well as the IκB kinase complex. The IKK complex then activates NF-κB signaling, which leads to the transcription of anti-apoptotic factors-such as FLIP and Bcl-XL-that promote cell survival. 

 

The formation of TNFR1 complex IIa and complex IIb depends on non-ubiquitylated RIPK1. For the formation of complex IIa, ubiquitylated RIPK1 in complex I is deubiquitylated by CYLD. This deubiquitylated RIPK1 dissociates from the membrane-bound complex and moves into the cytosol, where it interacts with TRADD, FADD, Pro-caspase 8 and FLIPL to form complex IIa. By contrast, complex IIb is formed when the RIPK1 in complex I is not ubiquitylated owing to conditions that have resulted in the depletion of cIAPs, which normally ubiquitylate RIPK1. This non-ubiquitylated RIPK1 dissociates from complex I, moves into the cytosol, and assembles with FADD, Pro-caspase 8, FLIPL and RIPK3 (but not TRADD) to form complex IIb. For either complex IIa or complex IIb to prevent necroptosis, both RIPK1 and RIPK3 must be inactivated by the cleavage activity of the Pro-caspase 8-FLIPL heterodimer or fully activated caspase 8. The Pro-caspase 8 homodimer generates active Caspase 8, which is released from complex IIa and complex IIb. This active Caspase 8 then carries out cleavage reactions to activate downstream executioner caspases and thus induce classical apoptosis. 

 

Formation of the complex IIc (necrosome) is initiated either by RIPK1 deubiquitylation mediated by CYLD or by RIPK1 non-ubiquitylation due to depletion of cIAPs, similar to complex IIa and complex IIb formation. RIPK1 recruits numerous RIPK3 molecules. They come together to form amyloid microfilaments called necrosomes. Activated RIPK3 phosphorylates and recruits MLKL, eventually leading to the formation of a supramolecular protein complex at the plasma membrane and necroptosis [1][2].

 

Reference:
[1]. Brenner D, et al. Regulation of tumour necrosis factor signalling: live or let die.Nat Rev Immunol. 2015 Jun;15(6):362-74. 
[2]. Conrad M, et al. Regulated necrosis: disease relevance and therapeutic opportunities.Nat Rev Drug Discov. 2016 May;15(5):348-66. 
 

TNF Receptor Isoform Comparison

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