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-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-P990939
    Podentamig
    		Inhibitor
    HY-P990939 is an CD3E/TNFRSF17-targeting VH-VH'-(scFv-heavy -λ) type chimeric antibody.
    Podentamig
  • HY-P99782
    Opinercept
    		Inhibitor
    Opinercept is a recombinant fusion protein comprising an TNFRSF1B fused to a human IgG1 Fc. 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 TNF-α receptor fusion protein that targets TNF-α. Tanfanercept is effective in ameliorating corneal erosions in a dry eye (DE) mouse model.
    Tanfanercept
  • HY-P991003
    Ingitamig
    		Inhibitor
    HY-P991003 is an TNFRSF17/KLRK1-targeting (G1_L-κ)_(G1-scFvkh_L-κ) type bispecific antibody.
    Ingitamig
  • 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-176234
    PDE4-IN-28
    		Inhibitor
    PDE4-IN-28 (Compound G1) is a PDE4D inhibitor (IC50: 29 nM). PDE4-IN-28 inhibits the production of TNF-α and NO (IC50: 13.32 and 2.32 μM, respectively). PDE4-IN-28 exhibits anti-inflammatory, antibacterial and analgesic effects in a rat pressure ulcer (PU) model and promotes HUVEC cell migration, thereby accelerating wound healing.
    PDE4-IN-28
  • HY-P991426
    MB-314
    		Activator
    MB-314 is a human IgG1 monoclonal antibody (mAb) targeting Lewis Y. MB-314 induces enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity. MB-314 increases the release of IFN-γ, TNF-α, MCP-1, and IL-6. MB-314 can be used in cancer research.
    MB-314
  • HY-P990531
    Anti-TNFSF9/4-1BBL Antibody
    The Anti-TNFSF9/4-1BBL Antibody is a CHO-expressed humanized antibody that targets TNFSF9/4-1BBL. The Anti-TNFSF9/4-1BBL Antibody has huIgG1 heavy chain and huκ light chain, with a predicted molecular weight (MW) of 150 kDa. For isotype control of the Anti-TNFSF9/4-1BBL Antibody, you can refer to Human IgG1 kappa, Isotype Control (HY-P99001).
    Anti-TNFSF9/4-1BBL Antibody
  • HY-175430
    TNF-α-IN-26
    		Inhibitor
    TNF-α-IN-26 (Compound 18) is a TNF-α inhibitor with an IC50 of 0.10  μM for CSBP ligands. TNF-α-IN-26 inhibits LPS (HY-D1056)-stimulated TNF production in mice model. TNF-α-IN-26 can be used for inflammatory diseases research.
    TNF-α-IN-26
  • HY-P3483
    Maxadilan
    		Inhibitor
    Maxadilan is a specific irreversible PAC1 receptor agonist and a potent vasodilator peptide present in the salivary glands of sand flies. Maxadilan exhibits anti-apoptotic activity in hADSCs. Maxadilan inhibits pro-inflammatory cytokines (TNF-α) and enhances anti-inflammatory mediators (IL-10). Maxadilan can activate leukocytes and inhibit vascular permeability through PAC1 receptors. Maxadilan promotes neural differentiation of human adipose-derived stem cells. Maxadilan can be used to study endotoxin shock, atherosclerosis, and neurodegenerative diseases[1][2][3][4][5].
    Maxadilan
  • 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-W012732R
    Isoquinoline (Standard)
    		Inhibitor
    Isoquinoline (Standard) is the analytical standard of Isoquinoline. This product is intended for research and analytical applications. Isoquinoline is an analog of pyridine. Isoquinoline structural-based alkaloids, such as tropoloisoquinoline, phthalideisoquinoline, and naphthylisoquinoline has anti-cancer activities.
    Isoquinoline (Standard)
  • HY-P990304A
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a)
    		Inhibitor
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a) is a mouse-derived IgG2a κ antibody inhibitor that targets mouse 4-1BBL/CD137L. Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a) is a chimeric version of the original TKS-1 antibody (HY-P990304). The variable domain sequences are identical to the original TKS-1 but the constant region sequences have been switched from rat IgG2a to mouse IgG2a. Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a) reacts with mouse 4-1BB ligand (4-1BBL). Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a) can be used for the researches of cancer, infection, inflammation and immunology.
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1-Mouse IgG2a)
  • HY-170492
    sEH inhibitor-19
    		Antagonist
    sEH inhibitor-19 (Compound (R)-14i) is an orally active inhibitor for soluble epoxide hydrolase (sEH) with an IC50 of 1.2 nM. sEH inhibitor-19 inhibits the expression of TNF-α and IL-6, exhibits anti-inflammatory activity in mouse acute pancreatitis or Carrageenan (HY-125474)-induced edema models.
    sEH inhibitor-19
  • HY-P990559
    BMS-986178
    BMS-986178 is a humanized antibody expressed in CHO, targeting TNFRSF4/OX40/CD134. BMS-986178 has a huIgG1 heavy chain and a huκ light chain, with a predicted molecular weight (MW) of 150 kDa. The isotype control for BMS-986178 can refer to Human IgG1 kappa, Isotype Control (HY-P99001).
    BMS-986178
  • HY-P991404
    AMG-228
    		Inhibitor
    AMG-228 is a human IgG1 monoclonal antibody (mAb) targeting TNFRSF18/GITR/CD357. AMG-228 can be used in advanced solid tumors research.
    AMG-228
  • 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-178012
    GLPG4471
    		Inhibitor
    GLPG4471 is a selective and orally active IRAK4 inhibitor with an IC50 of 1.7 nM. GLPG4471 exhibits potent inhibition of cytokine (TNFα and IFNα) secretion in cellular and whole blood phenotypic assays. GLPG4471 displays significant activity in a mouse model of collagen-induced arthritis. GLPG4471 can be used for the study of arthritis.
    GLPG4471
  • HY-P991405
    EU-102
    		Inhibitor
    EU-102 is a human monoclonal antibody (mAb) targeting TNFSF18. EU-102 can be used in solid tumors research.
    EU-102
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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