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-P99260
    Conatumumab
    		Agonist 98.90%
    Conatumumab (AMG 655) is a human monoclonal agonist antibody against human death receptor 5 (DR5, TRAILR2) (Kd: 1 nM for the long form of DR5, 0.8 nM for the short form of DR5). Conatumumab induces apoptosis via caspase activation. Conatumumab can be used in the research of cancers. .
    Conatumumab
  • HY-119307
    Apratastat
    		Inhibitor 99.67%
    Apratastat (TMI-005) is an orally active, non-selective and reversible TACE/MMPs inhibitor, can inhibit inhibit the release of TNF-α. Apratastat has the potential to overcome radiotherapy-resistance in non-small cell lung cancer (NSCLC). Apratastat is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
    Apratastat
  • HY-W010201
    Citronellol
    		Modulator 98.60%
    Citronellol ((±)-Citronellol) is an orally active inducer of apoptosis. Citronellol can prevent oxidative stress, mitochondrial dysfunction, and apoptosis in the SH-SY5Y cell Parkinson's disease model induced by 6-OHDA by regulating the ROS-NO, MAPK/ERK, and PI3K/Akt signaling pathways. Citronellol can induce necroptosis in human lung cancer cells through the TNF-α pathway and accumulation of ROS. Citronellol can reduce the levels of LC-3 and p62 to regulate the autophagy pathway, inhibit oxidative stress and neuroinflammation, and thus have neuroprotective effects on Parkinson's rats. Citronellol exhibits anti-fungal activity against Trichophyton rubrum by inhibiting ergosterol synthesis.
    Citronellol
  • HY-N4100
    Trilobatin
    		99.00%
    Trilobatin, a natural sweetener derived from Lithocarpus polystachyus Rehd, Trilobatin is an HIV-1 entry inhibitor targeting the HIV-1 Gp41 envelope. Neuroprotective effects. Trilobatin is also a SGLT1/2 inhibitor that selectively induces the proliferation of human hepatoblastoma cells.
    Trilobatin
  • HY-124750
    NecroX-7
    		Inhibitor 99.69%
    NecroX-7 is a potent free radical scavenger and a HMGB1 (high-mobility group box 1) inhibitor. NecroX-7 can be used as an antidote to acetaminophen toxicity. NecroX-7 exerts a protective effect by preventing the release of HMGB1 in ischemia/reperfusion injury. NecroX-7 inhibits the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. NecroX-7 can be used graft-versus-host disease (GVHD) research.
    NecroX-7
  • HY-156454
    UCB-6876
    		Inhibitor 99.96%
    UCB-6876 is a TNFα inhibitor and binds to asymmetrical crystal form of the TNF trimer (KD?=?22 μM).
    UCB-6876
  • HY-N0267
    Hypaconitine
    		Inhibitor 99.49%
    Hypaconitine, an active and highly toxic constituent derived from Aconitum species, is widely used to treat rheumatism.
    Hypaconitine
  • HY-19717
    DCVC
    		Inhibitor 99.83%
    DCVC (S-[(1E)-1,2-Dichloroethenyl]-L-cysteine) is a bioactive metabolite of trichloroethylene (TCE). DCVC inhibits pathogen-stimulated pro-inflammatory cytokines IL-1β, IL-8, and TNF-α release from tissue cultures.
    DCVC
  • HY-P99167
    Lucatumumab
    		Inhibitor 98.18%
    Lucatumumab (HCD122) is a fully human anti-CD40 antagonist monoclonal antibody, which blocks CD40/CD40L-mediated signaling. Lucatumumab efficiently mediates antibody-dependent cell-mediated cytotoxicity (ADCC) and clearance of tumor cells, can be used for refractory lymphomas, CLL and multiple myeloma research.
    Lucatumumab
  • HY-B0367
    Lornoxicam
    		Activator 99.36%
    Lornoxicam (Chlortenoxicam) is an orally active oxycontin nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, antipyretic and anticancer activities. Lornoxicam exhibits good inhibitory effects on both COX-1 and COX-2 (COX-1: IC50=0.005 μM; COX-2:IC50=0.008 μM) and inhibits the production of NO by iNOS (IC50=65 μM) and the proinflammatory cytokine IL-6 (IC50=54 μM). Lornoxicam also inhibits tumor cell proliferation and migration and induces tumor cell apoptosis. Lornoxicam can be used in the study of inflammatory pain, colorectal cancer and breast cancer.
    Lornoxicam
  • HY-118250
    GSK2245035
    		Activator 99.85%
    GSK2245035 is a highly potent and selective intranasal Toll-Like receptor 7 (TLR7) agonist with preferential Type-1 interferon (IFN)-stimulating properties. GSK2245035 has pEC50s of 9.3 and 6.5 for IFNα and TFNα. GSK2245035 effectively suppresses allergen-induced Th2 cytokine production in human peripheral blood cell cultures. GSK2245035 is used for asthma.
    GSK2245035
  • HY-N2086
    Ethyl palmitate
    		Inhibitor 99.05%
    Ethyl palmitate (Ethyl hexadecanoate) is a CHIKV virus inhibitor with an EC50 value of 0.0068 μM. Ethyl palmitate can reduce levels of TNF-α, IL-6, and NF-κB in endotoxemic rats, showing anti-inflammatory activity.
    Ethyl palmitate
  • HY-N0261
    Aurantio-obtusin
    		Inhibitor 99.89%
    Aurantio-obtusin is a anthraquinone compound that can be extracted from cassia seed. Aurantio-obtusin has the effects of decreasing blood pressure, decreasing blood lipids and anti-inflammatory.Aurantio-obtusin is an orally active vasodilator. Aurantio-obtusin ameliorates hepatic steatosis through AMPK/ autophagy- and AMPK/TFEB mediated inhibition of lipid accumulation.
    Aurantio-obtusin
  • HY-118922
    IW927
    		Antagonist 99.04%
    IW927 is a potent small molecule antagonist that blocks the binding of TNF-α to TNFRc1 with an IC50 value of 50 nM and disrupts TNFα-induced IκB phosphorylation with an IC50 value of 600 nM.
    IW927
  • HY-107390A
    AX-024 hydrochloride
    		Inhibitor 99.75%
    AX-024 hydrochloride is an orally available, first-in-class inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 ~1 nM. AX-024 hydrochloride modulates cell signaling by targeting SH3 domains. AX-024 hydrochloride has low-acute toxicity and high potency and selectivity, and strongly inhibit the production of IL-6, TNF-α, IFN-γ, IL-10 and IL-17A.
    AX-024 hydrochloride
  • HY-P9989
    Linvoseltamab
    		Inhibitor 99.71%
    Linvoseltamab is a bispecific antibody targeting to both BCMA (TNFRSF17) and CD3 epsilon. Linvoseltamab shows safety profile and encouraging efficacy in relapsed/refractory multiple myeloma (RRMM) models.
    Linvoseltamab
  • HY-N0616
    Trifolirhizin
    		99.91%
    Trifolirhizin is a pterocarpan flavonoid isolated from the roots of Sophora flavescens. Trifolirhizin possesses potent tyrosinase inhibitory activity with an IC50 of 506 μM. Trifolirhizin exhibits potential anti-inflammatory and anticancer activities.
    Trifolirhizin
  • HY-15507
    VGX-1027
    		Inhibitor 99.76%
    VGX-1027 is an orally active isoxazole compound that exhibits various immunomodulatory properties. VGX-1027 targets macrophages, reducing the production of the proinflammatory mediators TNF-α, IL-1β, IL-10. VGX-1027 has antidiabetogenic effects by limiting cytokine-mediated immunoinflammatory events.
    VGX-1027
  • HY-114360A
    Taurohyodeoxycholic acid sodium
    		Inhibitor 99.60%
    Taurohyodeoxycholic acid (THDCA) sodium is the taurine-conjugated form of the secondary bile acid hyodeoxycholic acid. Taurohyodeoxycholic acid can also reduce the activity and expression of myeloperoxidase TNF-α and IL-6, as well as colonic damage in TNBS-induced ulcerative colitis mouse model.
    Taurohyodeoxycholic acid sodium
  • HY-P99149
    Anti-Mouse TNFR2 Antibody (TR75-54.7)
    		Inhibitor
    Anti-Mouse TNFR2 Antibody is an anti-mouse TNFR2 IgG antibody inhibitor derived from host Armenian Hamster.
    Anti-Mouse TNFR2 Antibody (TR75-54.7)
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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