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 (45):

Cat. No. Product Name Effect Purity
  • HY-A0003
    Lenalidomide Inhibitor 99.98%
    Lenalidomide is a potent inhibitor of TNF-α used as a immunomodulatory drug. It has also been shown to have anti-angiogenic properties.
  • HY-16046
    Rimiducid Activator 99.05%
    Rimiducid (AP1903) is a dimerizer agent that acts by cross-linking the FKBP domains, initiating Fas signaling and hence apoptosis.
  • HY-10984
    Pomalidomide Inhibitor 99.86%
    Pomalidomide is an anti-angiogenic agent and an immunomodulator. Pomalidomide inhibits TNF-α release in LPS stimulated human PBMC with an IC50 of 13 nM.
  • HY-N0822
    Shikonin Inhibitor 99.80%
    Shikonin is a major component of a Chinese herbal medicine named zicao. Shikonin has shown various biological activities, including inhibition of TNF-α, NF-κB, HIV-1.
  • HY-15615A
    TIC10 Agonist 99.68%
    TIC10 is a potent, orally active, and stable TRAIL inducer which acts by inhibiting Akt and ERK, consequently activating Foxo3a and significantly inducing cell surface TRAIL .
  • HY-111255
    SPD304 Inhibitor >99.0%
    SPD304 is a selective inhibitor of tumor necrosis factor α (TNFα) and promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor, with an IC50 of 22 µM for inhibiting in vitro TNF receptor 1 (TNFR1) binding to TNF-α. SPD304 cannot be used in vivo due to its high toxicity.
  • HY-108847
    Etanercept Inhibitor
    Etanercept (Enbrel) is a tumor necrosis factor (TNF) inhibitor used for treating rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis.
  • HY-13812
    QNZ Inhibitor 98.46%
    QNZ (EVP4593) shows strong inhibitory effects on NF-κB transcriptional activation and TNF-α production with IC50s of 11 and 7 nM, respectively. QNZ (EVP4593) is a neuroprotective inhibitor of SOC channel.
  • HY-N0182
    Fisetin Inhibitor 98.02%
    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.
  • HY-A0003B
    Lenalidomide hemihydrate Inhibitor 99.82%
    Lenalidomide inhibits tumor angiogenesis, tumor proliferation and tumor secreted cytokines including TNF-α and IL 6.
  • HY-32018
    Cot inhibitor-2 Inhibitor 99.20%
    Cot inhibitor-2 is a COT/Tpl2 inhibitor.
  • HY-14622A
    Necrostatin 2 racemate Inhibitor 99.10%
    Necrostatin 2 is a potent necroptosis inhibitor with EC50 of 50 nM.
  • 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-N2027
    Taurochenodeoxycholic acid Inhibitor 99.80%
    Taurochenodeoxycholic acid is one of the main bioactive substances of animals' bile acid.
  • 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-107390A
    AX-024 hydrochloride Inhibitor 99.29%
    AX-024 hydrochloride is an cytokine release inhibitor which can strongly inhibit the production of interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), interferon-γ (IFN-γ), IL-10 and IL-17A.
  • HY-110203
    R-7050 Antagonist 98.83%
    R-7050 is a tumor necrosis factor receptor (TNFR) antagonist with greater selectivity toward TNFα.
  • HY-N0029
    Forsythoside B 99.99%
    Forsythoside B is a phenylethanoid glycoside isolated from the leaves of Lamiophlomis rotata Kudo, a Chinese folk medicinal plant for treating inflammatory diseases and promoting blood circulation. Forsythoside B could inhibit TNF-alpha, IL-6, IκB and modulate NF-κB.
  • HY-N0604
    Ginsenoside Rh1 Inhibitor 98.17%
    Ginsenoside Rh1 (Prosapogenin A2; Sanchinoside B2; Sanchinoside Rh1) is isolated from the root of Panax Ginseng. Ginsenoside Rh1 inhibits the expression of PPAR-γ, TNF-α, IL-6, and IL-1β.
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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