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-138793
    2-(2,6-Dioxopiperidin-3-yl)phthalimidine
    		Inhibitor 99.67%
    2-(2,6-Dioxopiperidin-3-yl)phthalimidine (EM-12), a teratogenic Thalidomide analogue, is more active than Thalidomide and is much more stable for hydrolysis. 2-(2,6-Dioxopiperidin-3-yl)phthalimidine enhances 1,2-dimethylhydrazine-induction of rat colon adenocarcinomas.
    2-(2,6-Dioxopiperidin-3-yl)phthalimidine
  • HY-P990124
    Anti-Mouse GITR Antibody (DTA-1)
    		Agonist 98.47%
    Anti-Mouse GITR Antibody (DTA-1) is a rat-derived IgG2b, λ type agonistic antibody, targeting to mouse GITR. The recommed isotype control of Anti-Mouse GITR Antibody (DTA-1) is Rat IgG2b kappa, Isotype Control (HY-P990682).
    Anti-Mouse GITR Antibody (DTA-1)
  • HY-124339
    JNJ525
    		Inhibitor
    JNJ525 (compound 1) is a TNFα inhibitor with the IC50 values of 1.2 μM and 1.1 μM against of TNFR1 and TNFR2, respectively.
    JNJ525
  • HY-P990040
    Exlinkibart
    		Inhibitor 99.66%
    Exlinkibart (LVGN-6051) targets TNFRSF9 and is an IgG1κ antibody humanized through complementarity-determining region (CDR) grafting technology.
    Exlinkibart
  • HY-P990067
    Evunzekibart
    		Inhibitor
    Evunzekibart (ATOR-1017) is an Fc-γ receptor conditional 4-1BB agonist and IgG4-type antibody. Evunzekibart can be used as monotherapy or in combination with anti-PD1 to exert anticancer activity.
    Evunzekibart
  • HY-P99605
    Cinrebafusp alfa
    		Inhibitor 98.53%
    Cinrebafusp alfa (PRS 343) is a high affinity CD137/HER2 bispecfic anticalin-based drug. Cinrebafusp alfa binds to recombinant human HER2 (Kd=0.3 nM) and human monomeric CD137 (4-1BB; Kd=5 nM). Cinrebafusp alfa facilitates T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation, further enhancing T-cell receptor-mediated activity and leading to tumor destruction. Cinrebafusp alfa has the potential for HER2+ solid tumors research.
    Cinrebafusp alfa
  • 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-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-N7064
    Iminostilbene
    		Inhibitor 99.34%
    Iminostilbene is a chemical precursor of carbamazepine. Additionally, Iminostilbene is an orally active inhibitor of PKM2 (Pyruvate Kinase M2) and COX2 (Cyclooxygenase-2). Iminostilbene exerts its effects by inhibiting PKM2 and its interaction with HIF-1α and STAT3, reducing COX2 and iNOS expression, and decreasing LPS-induced release of IL-1β, IL-6, TNF-α, and MCP-1, thereby suppressing macrophage-mediated inflammatory responses and improving myocardial ischemia/reperfusion (MI/R) injury. Iminostilbene holds promise for research in inflammation regulation, cardiovascular diseases (such as MI/R injury), and macrophage-mediated immune-related diseases.
    Iminostilbene
  • 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-N2036
    Mosloflavone
    		98.87%
    Mosloflavone is a flavonoid isolated from Scutellaria baicalensis Georgi with ?anti-EV71 activity. Mosloflavone? inhibits VP2 virus replication and protein expression during the initial stage of virus infection and inhibits viral VP2 capsid protein synthesis. Mosloflavone is a promising biocide and inhibits P. aeruginosa virulence and biofilm formation.
    Mosloflavone
  • 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-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-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
  • HY-P990907
    Brivekimig
    		Inhibitor 98%
    HY-P990907 is an TNFSF4/TNFSF2/ALB-targeting VH-VH-VH-VH-VH type chimeric antibody.
    Brivekimig
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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