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-112275
    TNF-α-IN-1
    Inhibitor 99.42%
    TNF-α-IN-1 is a TNF-α inhibitor extracted from patent US20030096841A1, compound example I-7.
    TNF-α-IN-1
  • HY-P99842A
    Dapirolizumab
    Inhibitor 99.40%
    Dapirolizumab is a monoclonal antibodi against CD40 ligand. Dapirolizumab targets CD40L, blocks its interaction with CD40 receptors, and inhibits adaptive immune activation. Dapirolizumab attenuates systemic lupus erythematosus.
    Dapirolizumab
  • 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
  • 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-15643A
    LY 303511 hydrochloride
    Activator 98.87%
    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.
    LY 303511 hydrochloride
  • 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-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-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-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-19929
    Tanimilast
    Antagonist 99.49%
    Tanimilast (CHF-6001) is an orally active and selective phosphodiesterase 4 inhibitor (IC50=0.026 nM) with robust anti-inflammatory activity and suitable for topical pulmonary administration. Tanimilast increases cellular cAMP levels, and inhibits NF-κB signaling pathway. Tanimilast is used for the research of obstructive lung diseases.
    Tanimilast
  • HY-W115786
    Kaolin
    Activator
    Kaolin is a family of kaolinitic clays, which is found in the earth's crust. Kaolin alleviates the toxicity of graphene oxide for mammalian cells. Kaolin can be utilized in industrial, cosmetic and medical fields, excipient.
    Kaolin
  • HY-P990151
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6)
    Inhibitor
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6) is a Armenian hamster-derived IgG type antibody inhibitor, targeting to mouse TL1A/TNFSF15.
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6)
  • HY-100735
    C 87
    Inhibitor 98.06%
    C 87 is a novel small-molecule TNFα inhibitor; potently inhibits TNFα-induced cytotoxicity with an IC50 of 8.73 μM.
    C 87
  • HY-P99119
    Anti-Mouse 4-1BB/CD137 Antibody (3H3)
    Inhibitor
    Anti-Mouse 4-1BB/CD137 Antibody (3H3) is an IgG2a antibody agonist against mouse 4-1BB, derived from a rat host, capable of stimulating 4-1BB signaling in vivo.
    Anti-Mouse 4-1BB/CD137 Antibody (3H3)
  • HY-P99257
    Bleselumab
    Inhibitor 98.97%
    Bleselumab (ASKP 1240) is a human anti-CD40 monoclonal antibody (mAb). Bleselumab binds to human CD40 with high affinity (Kd: 0.24 nM). Bleselumab inhibits immune responses by blocking the interaction of CD40 with its ligand CD40L. Bleselumab prevents organ transplant rejection.
    Bleselumab
  • HY-123630
    Allura Red AC
    Activator 98.01%
    Allura Red AC is a food colorant, appearing as a deep red water-soluble powder or granules, used in various applications such as beverages, syrups, candies, and cereals. Allura Red AC can statically quench the intrinsic fluorescence of HSA. Additionally, Allura Red AC is a 5-hydroxytryptamine (5-HT) pathway-associated pro-inflammatory agent, capable of exacerbating experimental colitis. Allura Red AC holds potential for research in inflammatory bowel disease (IBD), intestinal barrier function, and food additive safety.
    Allura Red AC
  • HY-N2263
    Skimmin
    99.64%
    Skimmin (Umbelliferone glucoside) is a major pharmacologically active and orally active molecule present in Hydrangea paniculata, a medical herb used in traditional Chinese medicine as an anti-inflammatory agent. Skimmin has renal protective activity. Skimmin can improve creatinine clearance, and reduce plasma creatinine, and kidney injuries. Skimmin has good anti-amoebic activity against the HM1:IMMS strain of Entamoeba histolytica. Skimmin has anti-cancer and neuroprotective activities. Skimmin reduces cardiac fibrosis as well as decreasing TNF-α, IL-6, IL1β, and TGFβ1 in cardiac tissues. Skimmin can be studied in research for diabetes and diabetes-related diseases.
    Skimmin
  • HY-154822
    DRI-C25441
    Inhibitor 99.53%
    DRI-C25441 is a potent blocker of CD40 and CD40L interaction, with an IC50 of 0.36 μM. DRI-C25441 can inhibit the immune response induced by alloantigen.
    DRI-C25441
  • HY-B0446
    Naphazoline hydrochloride
    Inhibitor 99.38%
    Naphazoline (Naphthazoline) hydrochloride is a potent α-adrenergic receptor agonist. Naphazoline hydrochloride reduces vascular hyperpermeability and promotes vasoconstriction. Naphazoline hydrochloride reduces the levels of inflammatory factors (TNF-α, IL-1β and IL-6), cytokines (IFN-γ and IL-4), IgE, GMCSF, and NGF. Naphazoline hydrochloride can be used for non-bacterial conjunctivitis research.
    Naphazoline hydrochloride
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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