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-W016412
    Coenzyme Q0
    		Inhibitor 99.79%
    Coenzyme Q0 (CoQ0) is a potent, oral active ubiquinone compound can be derived from Antrodia cinnamomea. Coenzyme Q0 induces apoptosis and autophagy, suppresses of HER-2/AKT/mTOR signaling to potentiate the apoptosis and autophagy mechanisms. Coenzyme Q0 regulates NFκB/AP-1 activation and enhances Nrf2 stabilization in attenuation of inflammation and redox imbalance. Coenzyme Q0 has anti-angiogenic activity through downregulation of MMP-9/NF-κB and upregulation of HO-1 signaling.
    Coenzyme Q0
  • 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-154821A
    DRI-C21041 (DIEA)
    		Inhibitor 99.07%
    DRI-C21041 DIEA is a CD40/CD40L interaction inhibitor, with an IC50 of 0.31 μM. DRI-C21041 DIEA inhibits the immune response induced by alloantigen.
    DRI-C21041 (DIEA)
  • HY-113402A
    Gamma-glutamylcysteine TFA
    		Inhibitor
    Gamma-glutamylcysteine (γ-Glutamylcysteine) TFA, an intermediate in glutathione (GSH) synthesis, is a dipeptide served as an essential cofactor for the antioxidant enzyme glutathione peroxidase (GPx). Gamma-glutamylcysteine TFA also upregulates the level of the anti-inflammatory cytokine IL-10 and reduces the levels of the pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). Gamma-glutamylcysteine TFA attenuates the changes in metalloproteinase activity in oligomeric Aβ40-treated astrocytes.
    Gamma-glutamylcysteine TFA
  • HY-P990706
    Povetacicept
    		Inhibitor ≥99.0%
    Povetacicept (ALPN-303), an Fc fusion protein of an engineered TACI domain, is a dual APRIL/BAFF antagonist. Povetacicept modulates B lymphocytes and pathogenic autoantibodies for the study of Lupus and other B cell-related autoimmune diseases.
    Povetacicept
  • HY-18377
    Bioymifi
    		Activator 98.0%
    Bioymifi (DR5 Activator), a potent TRAIL receptor DR5 activator, binds to the extracellular domain (ECD) of DR5 with a Kd of 1.2 μM. Bioymifi can act as a single agent to induce DR5 clustering and aggregation, leading to apoptosis.
    Bioymifi
  • HY-W012732
    Isoquinoline
    		Inhibitor 99.58%
    Isoquinoline is an analog of pyridine. Isoquinoline-based alkaloids, such as p-tolyl bisisoquinoline, phthaloyl isoquinoline, and naphthyl isoquinoline, exhibit anticancer activity. Berberine, an isoquinoline alkaloid, exerts anti-inflammatory effects in diabetic mice by downregulating the gene expression ratios of pro-/anti-inflammatory and Th1/Th2 cytokines. Additionally, some isoquinoline-based compounds also possess antidepressant, antibacterial, antimalarial, and anti-HIV activities.
    Isoquinoline
  • HY-N6850
    Calenduloside E
    		Inhibitor 99.07%
    Calenduloside E is a pentacyclic triterpenoid saponin that can be extracted from the bark and roots of Aralia ovata, and has anti-inflammatory and anti-apoptotic activities. Calenduloside E alleviates atherosclerosis by regulating macrophage polarization, improves mitochondrial function by regulating the AMPK-SIRT3 pathway, and alleviates acute liver injury. In addition, Calenduloside E promotes the interaction between L-type calcium channels and Bcl-2 related apoptosis genes, inhibits calcium overload, and alleviates myocardial ischemia/reperfusion injury. Calenduloside E also improves non-alcoholic fatty liver disease by regulating heat shock-dependent pathways, and inhibits ROS mediated JAK1-STAT3 pathways to reduce cellular inflammatory responses.
    Calenduloside E
  • HY-161982
    JNU-0921
    		Agonist 99.77%
    JNU-0921 is a potent and orally active CD137 agonist. JNU-0921 increases the mRNA expression of IFN-γ and GZMB. JNU-0921 induces luciferase activity with an EC50 value of 64.07 nM.JNU-0921 enhances effector and memory function of cytotoxic CD8+ T cells (CTLs) and alleviates their exhaustion. JNU-0921 also skews polarization of helper T cells toward T helper 1 type and enhances their activity to boost CTL function. JNU-0921 shows anticancer activity.
    JNU-0921
  • HY-19717
    DCVC
    		Inhibitor 99.78%
    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-N1482
    Methyl palmitate
    		98.0%
    Methyl palmitate is a naturally occurring fatty acid ester. Methyl palmitate is a potent inhibitor of ΙκB phosphorylation. Methyl palmitate modulates macrophage activity and down-regulates pro-inflammatory mediators such as TNF-α and nitric oxide (NO). Methyl palmitate possesses anti-inflammatory and antifibrotic effects. Methyl palmitate can inhibit LPS (HY-D1056)-induced Kupffer cells and rat peritoneal macrophages. Methyl palmitate is able to inhibit the phagocytic function of RAW cells. Methyl palmitate is antagonistic to muscarinic receptors. Methyl palmitate exerts cardioprotective effects against ischemia/reperfusion injury in vivo. Methyl palmitate is highly toxic against adult T. cinnabarinus.
    Methyl palmitate
  • HY-B1051
    Flumethasone
    		Inhibitor 99.84%
    Flumethasone (Flumetasone) is an orally active, high selective and potent glucocorticoid receptor (GR) agonist. Flumethasone activates GR to inhibit nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokine production (TNF-α, IL-1β) and promotes anti-inflammatory gene expression (IL-10), while also regulating metabolic enzyme activity (tyrosine aminotransferase induction). Flumethasone is promising for research of inflammatory diseases, cancer, and endocrine regulation.
    Flumethasone
  • HY-N2468
    Xylobiose
    		98.0%
    Xylobiose (1,4-β-D-Xylobiose; 1,4-D-Xylobiose) is an orally active Claudin 2/CLDN2 inhibitor and HSP27 inducer. Xylobiose works by regulating intestinal barrier function and glucose and lipid metabolism-related signaling pathways. Xylobiose inhibits CLDN2 expression to reduce intestinal permeability, induces HSP27 to enhance cell protection, and regulates the miR-122a/miR-33a axis to inhibit liver lipid synthesis and improve insulin resistance. Xylobiose can strengthen intestinal barrier integrity, reduce blood sugar and blood lipid levels, and reduce oxidative stress and inflammatory response. Xylobiose can be used in the study of type 2 diabetes and metabolic syndrome.
    Xylobiose
  • HY-135674
    SR-318
    		Inhibitor 98.17%
    SR-318, a chemical probe, is a potent and highly selective p38 MAPK inhibitor with IC50s of 5 nM, 32 nM and 6.11 μM for p38α, p38β and p38α/β, respectively. SR-318 potently inhibits the TNF-α release in whole blood with an IC50 of 283 nM. SR-318 has anti-cancer and anti-inflammatory activity.
    SR-318
  • HY-P99119
    Anti-Mouse 4-1BB/CD137 Antibody (3H3)
    		Inhibitor
    Anti-Mouse 4-1BB/CD137 Antibody (3H3) is an anti-mouse 4-1BB/CD137 IgG2a monoclonal antibody. Anti-Mouse 4-1BB/CD137 Antibody (3H3) can effectively activate memory T cells and inhibit tumors by increasing Bcl-xL and granzyme B levels. Anti-Mouse 4-1BB/CD137 Antibody (3H3) can be used for research on cancer such as lymphoma and colon cancer.
    Anti-Mouse 4-1BB/CD137 Antibody (3H3)
  • HY-P990070
    Zigakibart
    		Inhibitor 98.37%
    Zigakibart (BION-1301) is an IgG4-kappa, anti-TNFSF13 (tumor necrosis factor (TNF) superfamily member 13, APRIL, CD256) humanized monoclonal antibody. Zigakibart shows anti-inflammatory activity.
    Zigakibart
  • HY-N1508
    Ecliptasaponin A
    		Inhibitor 99.50%
    Ecliptasaponin A is an orally active pentacyclic triterpenoid saponin. Ecliptasaponin A exerts anti-tumor activity by activating ASK1/JNK pathway, inducing apoptosis and autophagy in lung cancer cells. Ecliptasaponin A exerts anti-inflammatory/anti-fibrotic effects and protects the cardiovascular system by inhibiting the HMGB1/TLR4/NF-κB pathway, and the expression of COX-2 and MMP-9. Ecliptasaponin A can enhance SOD activity, reduce MDA levels, and alleviate oxidative stress damage. Ecliptasaponin A exerts chondroprotective effects by inhibiting the expression of MMP13 and regulating inflammatory factors. Ecliptasaponin A improves ovarian function and regulates sex hormones by upregulating the expression of ESR1 receptors.
    Ecliptasaponin A
  • HY-B1197
    Amcinonide
    		Inhibitor 99.11%
    Amcinonide is an inhibitor of NO release (IC50 = 3.38 nM). Amcinonide inhibits NNC-induced expression of the proinflammatory genes iNOS, TNF-α, and IL-1β in glial cells. Amcinonide reduces the numbers of T6+/Ia+ cells with a concomitant increase in T6+/Ia- cells. Amcinonide induces a selective reduction in expression of Ia antigens. Amcinonide can also be studied in research for eczematous dermatitis.
    Amcinonide
  • HY-P990151
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6)
    		Inhibitor
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6) is an anti-mouse TL1A/TNFSF15 IgG monoclonal antibody. Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6) can reduce TL1A levels and block TL1A-DR3 interactions. Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6) can be used for research on inflammation conditions such as colitis and collagen-induced arthritis (CIA).
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6)
  • HY-118694
    TAPI-0
    		Inhibitor 98.98%
    TAPI-0 is a TACE (TNF-α converting enzyme; ADAM17) inhibitor with an IC50 of 100 nM. TAPI-0 is a MMP inhibitor and also attenuates TNF-α processing.
    TAPI-0
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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