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-117569
    KF24345 free base
    		Inhibitor
    KF24345 free base is an orally active adenosine uptake inhibitor. KF24345 free base inhibits adenosine uptake by human, mouse, rabbit and hamster erythrocytes with IC50 values of 59.5, 130.1, 104.2 and 30.9 nM, respectively. KF24345 free base has anti-inflammatory activity and can inhibit LPS-induced TNF-α production and leukopenia in mice.
    KF24345 free base
  • HY-N0633R
    Muscone (Standard)
    		Inhibitor
    Muscone (Standard) is the analytical standard of Muscone. This product is intended for research and analytical applications. Muscone is the main active monomer of traditional Chinese medicine musk. Muscone inhibits NF-κB and NLRP3 inflammasome activation. Muscone remarkably decreases the levels of inflammatory cytokines (IL-1β, TNF-α and IL-6), and ultimately improves cardiac function and survival rate.
    Muscone (Standard)
  • HY-P991393
    ASP8374
    		Activator
    ASP8374 is a human IgG4 monoclonal antibody (mAb) targeting TIGIT. ASP8374 increases IL-2 production in Jurkat cells and IFN-γ and TNF-α production in human PBMCs. ASP8374 can be used in advanced solid tumors research. Recommended isotype control: Human IgG4 kappa, Isotype Control (HY-P99003).
    ASP8374
  • HY-P990526
    Anti-TNFRSF21/DR6/CD358 Antibody
    		Inhibitor
    Anti-TNFRSF21/DR6/CD358 Antibody is a CHO-expressed humanized antibody that targets TNFRSF21/DR6/CD358. The Anti-TNFRSF21/DR6/CD358 Antibody has a huIgG1 heavy chain and a huκ light chain, with a predicted molecular weight (MW) of 150 kDa. The isotype control for Anti-TNFRSF21/DR6/CD358 Antibody can refer to Human IgG1 kappa, Isotype Control (HY-P99001).
    Anti-TNFRSF21/DR6/CD358 Antibody
  • HY-174405
    PROTAC PDE4 degrader-1
    		Inhibitor
    PROTAC PDE4 degrader-1 (Compound 9m) is a selective and orally active PDE4 PROTAC degrader with a DC50 of 41.98 μM. PROTAC PDE4 degrader-1 potently inhibits the secretion of pro-inflammatory cytokines such as TNF-α and IL-6. PROTAC PDE4 degrader-1 significantly alleviates pulmonary inflammation in LPS (HY-D1056)-induced acute lung injury (ALI) mice Model. Pink: PDE4 ligand (HY-174410); Blue: CRBN ligase ligand (HY-10984); Black: linker
    PROTAC PDE4 degrader-1
  • HY-N16066
    Candidusin A
    		Inhibitor
    Candidusin A (CHNQD-0803) (Compound 4) is a AMPK activator with a KD of 47.28 nM. Candidusin A can be isolated from marine fungus Aspergillus candidus. Candidusin A has cytotoxic activity and induces apoptosis in human prostate cancer cells (22Rv1, PC-3 and LNCaP cells). Candidusin A reduces adipogenesis genes expression and fat deposition, negatively regulates the NF-κB-TNFα inflammatory axis to suppress inflammation, and ameliorates liver injury and fibrosis. Candidusin A can be used for non-alcoholic steatohepatitis (NASH) research.
    Candidusin A
  • HY-P991324
    MEDI-7352
    		Inhibitor
    MEDI-7352 is a human bispecific antibody (bsAb) targeting NGF/bNGF & TNF. MEDI-7352 can be used in osteoarthritis (OA) pain research.
    MEDI-7352
  • HY-153690
    Progranulin modulator-1
    		Inhibitor
    Progranulin modulator-1 (Compound 60) is an orally active enhancer of progranulin (PGRN) secretion. Progranulin modulator-1 enhances the potency of BV-2 cell to increase PGRN levels, has inhibitory effect on hERG and Low cytotoxicity, the PGRN EC50 and hERG IC50 were 83 and 3100 nM, respectively.
    Progranulin modulator-1
  • HY-114538
    Asobamast
    Asobamast is a potent, orally active antiallergic agent that inhibits ige mediated passive pulmonary allergic responses in rats (ED50=4.7 mg/kg) and inhibits antigen-induced mediator release from sensitized guinea pig lung fragments.
    Asobamast
  • HY-168212
    PDE4-IN-22
    		Inhibitor
    PDE4-IN-22 (Compound 2e) is a PDE4 inhibitor with an IC50 value of 2.4 nM. PDE4-IN-22 exhibits anti-inflammatory activity and demonstrates significant anti-psoriatic effects in an Imiquimod (HY-B0180)-induced psoriasis mouse model.
    PDE4-IN-22
  • HY-N0212R
    Peimine (Standard)
    		Inhibitor
    Peimine (Standard) is the analytical standard of Peimine. This product is intended for research and analytical applications. Peimine (Verticine; Dihydroisoimperialine) is an orally active natural product. Peimine has anti-inflammatory, analgesic and cough relieving effects. Peimine can be used in cancer and inflammation related research.
    Peimine (Standard)
  • HY-P990657
    RG-7212 (RO5458640)
    		Inhibitor 99.62%
    RG-7212 (RO5458640) is a human-derived antibody expressed in CHO cells, targeting TNFSF12/TWEAK. RG-7212 (RO5458640) has a huIgG1 type heavy chain and a huκ type light chain, with a predicted molecular weight (MW) of 146.02 kDa. The isotype control for RG-7212 (RO5458640) can be referenced as Human IgG1 kappa, Isotype Control (HY-P99001).
    RG-7212 (RO5458640)
  • HY-P991439
    BIIB023
    		Inhibitor
    BIIB023 is a human monoclonal antibody (mAb) targeting TNFRSF12A/TWEAKR/CD266. BIIB023 can be used in lupus nephritis and rheumatoid arthritis research.
    BIIB023
  • HY-177338
    STING agonist-45
    		Agonist
    STING agonist-45 is a selective STING agonist (EC50 = 0.28 μM). STING agonist-45 activates the innate immune response through the cGAS-STING pathway, upregulating key markers such as p-TBK1 and IRF3. STING agonist-45 exhibits robust STING activation in human peripheral blood mononuclear cells (PBMCs), inducing the production of type I interferons (such as IFN-β) and downstream cytokines (such as TNF-α and IL-6). STING agonist-45 enhances anti-tumor immunity, inhibits tumor growth, and increases CD8+ T cell infiltration in mouse models. STING agonist-45 is promising for the study of STING-related diseases.
    STING agonist-45
  • HY-P991510
    CDX-1140
    		Agonist
    CDX-1140 is a human IgG2 CD40 agonist antibody. CDX-1140 activates dendritic cells (DCs) and B cells and drives NF-kB stimulation in a CD40-expressing reporter cell line. CDX-1140 is independent of FcR binding and synergistic with native CD40L signaling. CDX-1140 has both direct and immune-mediated anti-tumor activity. CDX-1140 can be used for the study of lymphoma cancer and solid tumors.
    CDX-1140
  • HY-P991151
    Opamtistomig
    		Inhibitor
    Opamtistomig is a humanized immunoglobulin (H-γ1-scFv-L-κ) dimer monoclonal antibody targeting human programmed death ligand 1 (PD-L1), CD274 and tumor necrosis factor receptor superfamily member 9 (TNFRSF9). Opamtistomig is promising for research of various solid tumors and hematological malignancies.
    Opamtistomig
  • HY-172430S
    Epaldeudomide
    		Antagonist
    Epaldeudomide (Compound A406) is the inhibitor for TNF-α (>50% inhibition rate at 100 nM). Epaldeudomide inhibits the proliferation of cancer cells MM.1S (IC50 < 300 nM), WSU-DLCL-2 (IC50 < 100 nM) and Rec-1 (IC50 < 100 nM). Epaldeudomide exhibits antineoplastic activity.
    Epaldeudomide
  • HY-157147
    NLRP3-IN-24
    NLRP3-IN-24 (Compounds 15a) is an inhibitor against NLRP3. NLRP3-IN-24 has an inhibitory effect on the activation of NLRP3 inflammasome.
    NLRP3-IN-24
  • HY-P990678
    Vonlerizumab
    Vonlerizumab is a CHO-expressed humanized antibody targeting TNFRSF4/OX40/CD134. Vonlerizumab carries a huIgG1 heavy chain and a huκ light chain, with a predicted molecular weight (MW) of 145.22 kDa. The isotype control for Vonlerizumab can refer to Human IgG1 kappa, Isotype Control (HY-P99001).
    Vonlerizumab
  • HY-146435
    Anti-inflammatory agent 22
    		Inhibitor
    Anti-inflammatory agent 22 (compound 14a) is an orally active anti-inflammatory agent. Anti-inflammatory agent 22 inhibits LPS-induced TNF-α production with an IC50 value of 14.6 μM. Anti-inflammatory agent 22 has preventive effects on lymphedematous tissue via suppression of adipogenesis. Anti-inflammatory agent 22 suppresses limb lymphedema volume in mice.
    Anti-inflammatory agent 22
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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