1. Apoptosis
  2. TNF Receptor

TNF Receptor

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.

View TNF Receptor Pathway Map

TNF Receptor Related Products (41):

Cat. No. Product Name Effect Purity
  • HY-A0003
    Lenalidomide Inhibitor 99.98%
    Lenalidomide is a potent inhibitor of TNF-α and has antiangiogenic effect.
  • HY-16046
    AP1903 Activator 99.05%
    AP1903 is a homodimer binding to FKBP, elicits potent and dose-dependent apoptotic death of engineered cell line HT1080 in culture with an EC50 of 0.1 nM. AP1903 induces Fas activation. Fas receptor also known as tumor necrosis factor receptor superfamily member 6 (TNFRSF6).
  • HY-10984
    Pomalidomide Inhibitor 99.86%
    Pomalidomide is a known inhibitor of TNF-α release in LPS stimulated human PBMC with IC50 of 13 nM.
  • HY-N0822
    Shikonin Inhibitor 99.64%
    Shikonin is an inhibitor of TMEM16A chloride channel with an IC50 of 6.5 μM. Shikonin is also a specific inhibitor of PKM2 and can also inhibit tumor necrosis factor-α (TNF-α) and prevent activation of nuclear factor-κB (NF-κB) pathway.
  • HY-15615A
    TIC10 Agonist 99.68%
    TIC10 is a potent, orally active, and stable TRAIL inducer, also inhibits Akt and ERK activity.
  • HY-110203
    R-7050 Antagonist 98.83%
    R-7050 is a tumor necrosis factor receptor (TNFR) antagonist with greater selectivity toward TNFα.
  • HY-N0066
    Eucalyptol Inhibitor >98.0%
    Eucalyptol is an inhibitor of 5-HT3 receptor ,potassium channel, TNF-α and IL-1β.
  • HY-N0509
    Astilbin Inhibitor 99.43%
    Astilbin, a flavonoid compound, is isolated from the rhizome of Smilax glabra. Astilbin enhances NRF2 activation. Astilbin also suppresses TNF-α expression and NF-κB activation.
  • HY-13812
    QNZ Inhibitor 98.46%
    QNZ shows strong inhibitory effects on NF-κB transcriptional activation and TNF-α production with IC50s of 11 and 7 nM, respectively. EVP4593 is a neuroprotective inhibitor of SOC channel.
  • HY-A0003B
    Lenalidomide hemihydrate Inhibitor 99.82%
    Lenalidomide hemihydrate is a potent inhibitor of TNF-α and has antiangiogenic effect.
  • HY-14622
    Necrostatin 2 Inhibitor 99.97%
    Necrostatin 2 is a potent necroptosis inhibitor. EC50 for inhibition of necroptosis in FADD-deficient Jurkat T cells treated with TNF-α is 0.05 μM.
  • HY-N0182
    Fisetin Inhibitor >98.0%
    Fisetin is a natural flavonol found in many fruits and vegetables with various benefits, such as antioxidant, anticancer, neuroprotection effects.
  • HY-P0224
    N-Formyl-Met-Leu-Phe Inhibitor 99.46%
    N-Formyl-Met-Leu-Phe (fMLP; N-Formyl-MLF) is a chemotactic peptide and a specific ligand of N-formyl peptide receptor (FPR). N-Formyl-Met-Leu-Ph is reported to inhibit TNF-alpha secretion. Sequence: .
  • HY-N2027
    Taurochenodeoxycholic acid Inhibitor 99.80%
    Taurochenodeoxycholic acid is one of the main bioactive substances of animals' bile acid.
  • HY-14622A
    Necrostatin 2 racemate Inhibitor 99.10%
    Necrostatin 2 is a potent necroptosis inhibitor with EC50 of 50 nM.
  • HY-32018
    Cot inhibitor-2 Inhibitor 99.20%
    Cot inhibitor-2 is a COT/Tpl2 inhibitor.
  • HY-100735
    C 87 Inhibitor >98.0%
    C87 is a novel small-molecule TNFα inhibitor; potently inhibits TNFα-induced cytotoxicity with an IC50 of 8.73 μM.
  • HY-15643A
    LY 303511 hydrochloride Activator 98.41%
    LY 303511 hydrochloride is a structural analogue of LY294002. LY303511 does not inhibit PI3K. LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells. LY303511 reversibly blocks K+ currents (IC50=64.6±9.1 μM) in MIN6 insulinoma cells.
  • HY-N0724
    Mesaconitine Inhibitor 99.55%
    Mesaconitine is the main active component of genus aconitum plants.
  • HY-N0297
    Sinensetin Inhibitor 99.22%
    Sinensetin is a methylated flavone found in certain citrus fruits. pocess potent antiangiogenesis and anti-inflammatory, sinensetin enhances adipogenesis and lipolysis.
tnf-receptor-map.png

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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