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-P99321
    Teneliximab
    		Inhibitor ≥99.0%
    Teneliximab (BMS-224819) is a chimeric monoclonal antibody, blocks the CD40-CD40L interaction. Teneliximab (BMS-224819) has partial agonist activity resulting in some signaling through CD40 and peripheral B cell depletion.
    Teneliximab
  • 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-P99669
    Iratumumab
    		Inhibitor 98.95%
    Iratumumab (MDX-060) a human anti-CD30 IgG1κ monoclonal antibody. Iratumumab inhibits the growth of CD30-expressing tumor cells. Iratumumab can be used for research of Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL).
    Iratumumab
  • HY-101170
    BU224 hydrochloride
    		Inhibitor
    BU224 hydrochloride is a selective and high affinity imidazoline I2 receptor ligand, with a Ki of 2.1 nM. BU224 hydrochloride is sometimes used as an I2 receptor antagonist. BU224 hydrochloride exerts neuroprotective effects, with anti-inflammatory and anti-apoptotic properties. BU224 hydrochloride improves memory in 5XFAD mice, enlarging dendritic spines and reducing Aβ-induced changes in NMDARs. BU224 hydrochloride can be used for Alzheimer's disease research.
    BU224 hydrochloride
  • HY-164102
    TNF-α-IN-18
    		Inhibitor 98.94%
    TNF-α-IN-18 (Compound 61) is an inhibitor for TNF-α (IC50 of 1.8 μM), that inhibits TNF signaling pathway through block of NF-kB migration from cytoplasm to nucleus. TNF-α-IN-18 exhibits slight cytotoxicity to mouse fibroblast LM cell, with a CC50 >50 μM. TNF-α-IN-18 ameliorates the TNF- or Lipopolysaccharide (HY-D1056)-induced sepsis in mouse models. TNF-α-IN-18 protects mice from rheumatoid arthritis.
    TNF-α-IN-18
  • HY-N8435
    Desoxo-narchinol A
    		Inhibitor ≥98.0%
    Desoxo-narchinol A is an orally active and potent anti-inflammatory agent. Desoxo-narchinol A can be isolated from the roots and rhizomes of Nardostachys jatamansi. Desoxo-narchinol A can be used for septic shock and inflammatory diseases research.
    Desoxo-narchinol A
  • HY-15790H
    (S)-Elobixibat
    		Inhibitor 98.75%
    (S)-Elobixibat is the S enantiomer of Elobixibat (HY-15790). (S)-Elobixibat is an orally effective Apical Sodium-Dependent Bile (IBAT) inhibitor. (S)-Elobixibat decreases LDL cholesterol, increases serum GLP-1, promotes colon motility, and has the potential to treat metabolic syndrome. (S)-Elobixibat can be used to study constipation, dyslipidemia, non-alcoholic hepatitis, and liver tumors.
    (S)-Elobixibat
  • HY-P1875A
    TNF-α (46-65), human TFA
    		99.90%
    TNF-α (46-65), human (TFA) is a peptide of human TNF-α.
    TNF-α (46-65), human TFA
  • HY-N3595
    Cleomiscosin A
    		Inhibitor 99.15%
    Cleomiscosin A is a coumarino-lignoid from branch of Macaranga adenantha. Cleomiscosin A is active against TNF-alpha secretion of the mouse peritoneal macrophages.
    Cleomiscosin A
  • HY-125025
    SMI 6860766
    		Inhibitor
    SMI 6860766, a small molecule inhibitor of CD40-TRAF6 interaction, improves glucose tolerance, reduces immune cell accumulation in adipose tissue, and reduces AT inflammation.
    SMI 6860766
  • HY-P99425
    Afelimomab
    		99.34%
    Afelimomab (MAK 195F) is an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment. Afelimomab can be used for the research of sepsis.
    Afelimomab
  • HY-P1860A
    TNF-α (31-45), human TFA
    		Activator
    TNF-α (31-45), human TFA is a potent NF-kB pathway activator. TNF-αis a proinflammatory cytokine that induces necrosis or apoptosis. TNF alpha stimulates NF-κB pathway via TNFR2 promotes cancer growth, invasion, and metastasis.
    TNF-α (31-45), human TFA
  • HY-156817
    TNIK-IN-6
    		Inhibitor
    TNIK-IN-6 (Compound 9) is an inhibitor of Traf2 and Nck-interacting kinase (TNIK) and , with IC50 of 0.93 μM, that plays important roles in neurological and psychiatric disorders.
    TNIK-IN-6
  • HY-P99663
    Inezetamab
    		Inhibitor 99.77%
    Inezetamab is a bispecific anti-CD40 and anti-MSLN IgG1 monoclonal antibody.
    Inezetamab
  • HY-N1195
    Sugiol
    		Inhibitor 99.88%
    Sugiol is an abietane diterpenoid, can be isolated from Calocedrus formosana bark. Sugiol has anti-inflammatory activity, could effectively reduce intracellular reactive oxygen species (ROS) production in lipopolysaccharide (LPS)-stimulated macrophages.
    Sugiol
  • HY-N0247
    Saikosaponin B1
    		Inhibitor 99.42%
    Saikosaponin B1 is a bioactive constituent of Radix Bupleuri. Saikosaponin B1 is an agonist of the 5-HT2C receptor with an EC50 of 147.41 μM. Saikosaponin B1 inhibits the Hedgehog (Hh) signaling pathway by targeting the transmembrane protein SMO. Sailosaponin B1 can reduce liver fibrosis. Saikosaponin B1 has anti-cancer activities thus can be studies in research for cancers such as Medulloblastoma (MB).
    Saikosaponin B1
  • HY-113763
    TWEAK-Fn14-IN-1
    		Inhibitor 98.59%
    TWEAK-Fn14-IN-1 (Compound L524-0366) is a specific dose-dependent TWEAK-Fn14 inhibitor. TWEAK-Fn14-IN-1 binds specifically to the Fn14 surface with a KD of 7.12 μM. TWEAK-Fn14-IN-1 inhibits TWEAK induced glioma cell migration without any potential cytotoxic effects.
    TWEAK-Fn14-IN-1
  • HY-P9980A
    Belantamab (FUT8-KO)
    		98.10%
    Belantamab (FUT8-KO) is an anti-BCMA (TNFRSF17) monoclonal antibody expressed by CHO cells with the fucosyltransferase 8 gene (FUT8) knocked out. Fucose deficiency enhances the ADCC effect of the antibody. Belantamab (FUT8-KO) can be used to synthesize antibody-active molecule conjugate (ADC), Belantamab mafodotin.
    Belantamab (FUT8-KO)
  • HY-W013636C
    2-Ketoglutaric acid potassium
    		Inhibitor ≥98.0%
    2-Ketoglutaric acid (Alpha-Ketoglutaric acid) (potassium) is an intermediate in the production of ATP or GTP in the Krebs cycle. 2-Ketoglutaric acid potassium is a reversible and orally active inhibitor of tyrosinase with an IC50 value of 15 mM. 2-Ketoglutaric acid potassium also acts as the major carbon skeleton for nitrogen-assimilatory reactions. 2-Ketoglutaric acid potassium significantly suppresses abnormal intestinal permeability, delocalization of tight junction proteins from the intestinal cells, expression of TNFα in vitro and in vivo. 2-Ketoglutaric acid potassium directly binds to TAK1, and inhibits the TRAF6-TAK1 interaction. 2-Ketoglutaric acid potassium also alleviates inflammatory bowel disease (IBD) symptoms and gut microbiota dysbiosis, evident by the improvements in the intestine length.
    2-Ketoglutaric acid potassium
  • HY-P991052
    GSK-3174998
    		Inhibitor 99.81%
    GSK-3174998 is a humanized IgG1 OX40/TNFRSF4 agonistic monoclonal antibody. GSK-3174998 has the potential for the study of advanced solid tumors. The isotype control for GSK-3174998 can refer to Human IgG1 kappa, Isotype Control (HY-P99001).
    GSK-3174998
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. 
 

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