1. Signaling Pathways
  2. Apoptosis
  3. TNF Receptor

TNF Receptor

Tumor Necrosis Factor Receptor; TNFR

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.

Cat. No. Product Name Effect Purity Chemical Structure
  • 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-P99825
    Relfovetmab
    Inhibitor
    Relfovetmab is an anti-NGF monoclonal antibody (mAb).
    Relfovetmab
  • 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-P99820
    Ranevetmab
    Ranevetmab (NV-01) is a caninised anti-NGF monoclonal antibody (mAb). Ranevetmab can alleviate pain, and is used for the research of degenerative joint disease (DJD) pain.
    Ranevetmab
  • 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-169731
    RO27-3225 trifluoroacetate
    Inhibitor
    RO27-3225 trifluoroacetate is a peptide agonist of melanocortin receptor 4 (MC4R) with neuroprotective and anti-inflammatory activity with an EC50 value of 1 nM, while 8 nM for MC1R. RO27-3225 trifluoroacetate reverses hemorrhagic shock, reduces brain edema, blood-brain barrier (BBB) permeability, and hippocampal IL-1β and TNF-α levels in a rat model of intra-abdominal hypertension induced by hemorrhagic shock and resuscitation.
    RO27-3225 trifluoroacetate
  • 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
  • HY-121401
    Myrtenal
    Myrtenal ((±)-Myrtenal) is a monoterpene that acts as an antineoplastic agent. Myrtenal inhibits liver cancer by preventing DEN-PB-induced upregulation of TNF-α protein expression.
    Myrtenal
  • HY-12385
    Ximoprofen
    Inhibitor
    Ximoprofen is a propionic nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory property. Ximoprofen can be used for ankylosing spondylitis research.
    Ximoprofen
  • HY-N0152R
    Myricitrin (Standard)
    Inhibitor
    Myricitrin (Standard) is the analytical standard of Myricitrin. This product is intended for research and analytical applications. Myricitrin, a naturally occurring flavonoid, is an orally active nitric oxide (NO) and PKC inhibitor. Myricitrin has central nervous system activity, including anxiolytic-like action. Myricitrin possesses antioxidant, anti-inflammatory, antifibrotic and anti-malarial effects.
    Myricitrin (Standard)
  • HY-119866
    β-Alethine
    β-Alethine is a disulfide that can be used as an anti-tumor agent and immune adjuvant.
    β-Alethine
  • HY-172870
    PDE4B-IN-4
    Inhibitor
    PDE4B-IN-4 (Compound 11E) is a PDE4B (IC50: 2.82 nM) and TNF-α (IC50: 7.20 nM) inhibitor. PDE4B-IN-4 inhibits neutrophilia in a mouse lipopolysaccharide (LPS)-induced sepsis model and exhibits anti-inflammatory activity.
    PDE4B-IN-4
  • HY-P991406
    MK-1248
    Inhibitor
    MK-1248 is a human IgG4 monoclonal antibody (mAb) targeting TNFSF18. MK-1248 enhances the proliferative response of tumor-infiltrating lymphocytes to anti-CD3 stimulation and promotes the production of anti-tumor-associated regulatory cytokines. MK-1248 can be used in solid tumors research.
    MK-1248
  • HY-144737
    Anti-inflammatory agent 15
    Inhibitor
    Anti-inflammatory agent 15 (compound 29) is a potent antimycobacterial and anti-inflammatory agent. Anti-inflammatory agent 15 inhibits Mtb H37Rv and M299 growth, with MIC50 (minimum inhibitory concentration 50%) of 2.3 and 7.8 μM, respectively. Anti-inflammatory agent 15 inhibits NO through the suppression of iNOS expression, and also inhibited the production of TNF-α and IL-1β. Anti-inflammatory agent 15 can be used for tuberculosis (TB) research.
    Anti-inflammatory agent 15
Cat. No. Product Name / Synonyms Species Source
Cat. No. Product Name / Synonyms Application Reactivity

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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