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-B0809
    Theophylline
    		Inhibitor 99.97%
    Theophylline (1,3-Dimethylxanthine) is a potent phosphodiesterase (PDE) inhibitor, adenosine receptor antagonist, and histone deacetylase (HDAC) activator. Theophylline (1,3-Dimethylxanthine) inhibits PDE3 activity to relax airway smooth muscle. Theophylline (1,3-Dimethylxanthine) has anti-inflammatory activity by increase IL-10 and inhibit NF-κB into the nucleus. Theophylline (1,3-Dimethylxanthine) induces apoptosis. Theophylline (1,3-Dimethylxanthine) can be used for asthma and chronic obstructive pulmonary disease (COPD) research.
    Theophylline
  • HY-B1272
    Desipramine hydrochloride
    		99.76%
    Desipramine hydrochloride is a first-generation tricyclic antidepressant. Desipramine hydrochloride selectively binds to norepinephrine transporter and blocks neuronal norepinephrine reuptake. Desipramine hydrochloride activates MAPK signaling via ERK1/2, JNK, and p38, represses NF-κB and AP-1 activity, and induces apoptosis via ROS elevation, mitochondrial membrane potential reduction, and intracellular calcium increase. Desipramine hydrochloride also shows anyi-inflammatory activity, inhibiting TNF-α production. Desipramine hydrochloride can be used for the research of hepatocellular cancer, inflammation, and neurological diseases.
    Desipramine hydrochloride
  • HY-P990876
    Afimkibart
    		Inhibitor 99.59%
    Afimkibart (PF-06480605; RVT-3101) is a fully human monoclonal antibody that selectively inhibits trimeric tumor necrosis factor-like ligand 1A (TL1A). Afimkibart neutralizes active trimeric TL1A, blocks TL1A-induced signaling pathways. Afimkibart inhibits NF-κB activation and IFN-γ production. Afimkibart can be used for the research of inflammatory bowel disease.
    Afimkibart
  • HY-N0136
    Taxifolin
    		99.92%
    Taxifolin ((+)-Dihydroquercetin) exhibits important anti-tyrosinase activity. Taxifolin exhibits significant inhibitory activity against collagenase with an IC50 value of 193.3 μM. Taxifolin is an important natural compound with antifibrotic activity. Taxifolin is a free radical scavenger with antioxidant capacity.
    Taxifolin
  • HY-B0190A
    Nafamostat mesylate
    		99.94%
    Nafamostat mesylate (FUT-175), an anticoagulant, is a synthetic serine protease inhibitor. Nafamostat mesylate has anticancer and antivirus effect. Nafamostat mesylate induce apoptosis by up-regulating the expression of tumor necrosis factor receptor-1 (TNFR1). Nafamostat mesylate can be used in the development of the pathological thickening of the arterial wall.
    Nafamostat mesylate
  • HY-110203
    R-7050
    		Antagonist 99.96%
    R-7050 (TNF-α Antagonist III) is a tumor necrosis factor receptor (TNFR) antagonist with greater selectivity toward TNFα.
    R-7050
  • HY-12085
    Apremilast
    		Inhibitor 99.87%
    Apremilast (CC-10004) is an orally available inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4) with an IC50 of 74 nM. Apremilast inhibits TNF-α release by lipopolysaccharide (LPS) with an IC50 of 104 nM.
    Apremilast
  • HY-13687
    IKK 16
    		Inhibitor 99.88%
    IKK 16 is an orally active IKK inhibitor. IKK 16 shows IC50s of 40 nM, 70 nM, 200 nM, and 50 nM for IKK2, IKK complex, IKK1, and LRRK 2, respectively. IKK 16 is also a pan-PKD inhibitor, inhibiting PKD1, PKD2, and PKD3 with IC50s of 153.9, 115, and 99.7 nM, respectively. IKK 16 is also an ABCB1 inhibitor, interfering with the binding of ABCB1 to its substrates. IKK 16 protects against LPS (HY-D1056)-induced multiple organ dysfunction by reducing the acute inflammatory response induced by endotoxin exposure. IKK 16 can restore renal function and alleviate fibrosis in acute kidney injury. IKK 16 attenuates cardiac dysfunction associated with polymicrobial sepsis in mice with type 2 diabetes mellitus (T2DM) by inhibiting the NF-κB pathway.
    IKK 16
  • HY-113402
    Gamma-glutamylcysteine
    		Inhibitor 98.53%
    Gamma-glutamylcysteine (γ-Glu-Cys) is an orally active, blood-brain barrier permeable dipeptide. Gamma-glutamylcysteine activates AMPK, SIRT1, IL-4/STAT6, AC/cAMP/PI3K, IGF-1R/IRS1/PI3K, and Nrf2 signaling pathways; it inhibits NF-κB, JAK1/STAT1/3, MAPKs, cadmium-induced p38 MAPK, JNK, and PI3K/Akt signaling pathways. Gamma-glutamylcysteine regulates macrophage polarization, modulates the trafficking of CD36 and GLUT4, induces glutathione synthesis, improves metabolic dysfunction, reduces lipid deposition, ameliorates glucose homeostasis, inhibits apoptosis (Apoptosis), stabilizes mitochondria, suppresses lipid peroxidation, iron accumulation and ferroptosis (Ferroptosis), reduces ds-HMGB1 levels, reverses mechanical hyperalgesia, and alleviates hepatic lipid droplet formation. Gamma-glutamylcysteine is applicable to research related to inflammatory bowel disease, type 2 diabetes, cadmium-induced neurotoxicity, Alzheimer's disease, cerebral ischemia/reperfusion injury, neuropathy, and alcoholic liver disease.
    Gamma-glutamylcysteine
  • HY-B1670A
    (-)-Isoproterenol hydrochloride
    		Inhibitor 99.97%
    (-)-Isoproterenol (Levisoprenalinel) hydrochloride is the R-isomer of Isoproterenol. (-)-Isoproterenol hydrochloride can reduce the cleavage of caspase 3 and TNFα levels in retinal endothelial cells (REC). (-)-Isoproterenol hydrochloride can be used for the study of diabetic retinopathy.
    (-)-Isoproterenol hydrochloride
  • HY-160412
    Balinatunfib
    		Inhibitor 99.94%
    Balinatunfib (SAR-441566) is an orally active inhibitor of TNFR1 signaling. By binding to the central pocket of the soluble TNFα (sTNFα) trimer, Balinatunfib stabilizes an asymmetric conformation, blocking its binding to TNFR1 (without affecting TNFR2) and thus inhibiting downstream pathways. Balinatunfib has anti-inflammatory activity, and can be used in the study of autoimmune diseases.
    Balinatunfib
  • HY-P9980
    Belantamab
    		Inhibitor 99.90%
    Belantamab (GSK2857916) is a humanized IgG1 anti-BCMA/TNFRSF17 monoclonal antibody. Belantamab is linked to MMAF (HY-15579) through a non-cleavable ADC linker to synthesize the antibody-active molecule conjugate (ADC) Belantamab mafodotin (HY-P3239). After binding to BCMA on the surface of tumor cells, Belantamab mafodotin enters the cell through receptor-mediated endocytosis. After entering the cell, Belantamab mafodotin releases MMAF, blocks cell division by inhibiting tubulin polymerization, arrests the cell cycle and induces cell apoptosis. Belantamab can be used for the study of multiple myeloma, especially relapsed/refractory multiple myeloma.
    Belantamab
  • HY-P9952
    Belimumab
    		Inhibitor 99.40%
    Belimumab (LymphoStat B) is a humanized IgG1λ monoclonal antibody against B-lymphocyte stimulator (BLyS) protein. Belimumab antagonizes BLyS activity in autoimmune diseases and B-lymphocyte malignancies. Belimumab can be used for systemic lupus erythematosus (SLE) research. The component ratio of this product is Active ingredient: Excipients = 1:1.0-1:1.2.
    Belimumab
  • HY-123942
    Diprovocim
    		Agonist 98.82%
    Diprovocim is a potent TLR1/TLR2 agonist. Diprovocim elicits full agonist activity in human THP-1 cells (EC50=110 pM). Diprovocim stimulates the release of TNF-α from mouse macrophages (EC50=1.3 nM). Diprovocim activates downstream MAPK and NF-κB signaling pathway. Diprovocim displays strong adjuvant activity in mice, particularly abetting cellular immune responses.
    Diprovocim
  • HY-13812
    QNZ
    		Inhibitor 99.50%
    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.
    QNZ
  • HY-120934
    C25-140
    		Inhibitor 99.92%
    C25-140, a first-in-class, orally active, and fairly selective TRAF6-Ubc13 inhibitor, directly binds to TRAF6, and blocks the interaction of TRAF6 with Ubc13. C25-140 lowers TRAF6 activity, reduces NF-κB activation, and combats autoimmunity.
    C25-140
  • HY-P9979
    Rozanolixizumab
    		Inhibitor 99.34%
    Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), is used to the research of reducing pathogenic IgG in autoimmune and alloimmune diseases.
    Rozanolixizumab
  • HY-16657
    TAPI-1
    		Antagonist 99.36%
    TAPI-1 is a broad-spectrum MMP inhibitor and NF-κB p65 inhibitor that targets ADAM17/TACE, ADAM10 and other proteins. TAPI-1 reduces the proteolytic cleavage of membrane-bound TNF-α, decreases TNF-α levels, inhibits NF-κB pathway activation, and downregulates profibrotic markers. TAPI-1 reduces the proportion of proinflammatory immune cells, alleviates cardiac and airway fibrosis, and improves cardiac function after myocardial infarction. Meanwhile, TAPI-1 inhibits the viability, migration and invasion of esophageal squamous cell carcinoma cells, enhances the chemosensitivity of Cisplatin (HY-17394), induces apoptosis, and shows low toxicity to normal esophageal epithelial cells. TAPI-1 can be widely used in studies related to myocardial infarction-induced heart failure, severe traumatic tracheal stenosis, esophageal squamous cell carcinoma and other conditions.
    TAPI-1
  • HY-B0539
    Desloratadine
    		Inhibitor 99.98%
    Desloratadine (Sch34117) is an orally active and selective H1 receptor antagonist (Ki=0.9 nM) with anti-inflammatory and anti-allergic activities. Desloratadine inhibits the release of histamine and LTC4 from human basophils and targets the regulatory signals of IL-4 and IL-13 production in basophils. Desloratadine significantly alleviates SAR symptoms in patients with concurrent asthma and can be used in the study of seasonal allergic rhinitis and chronic idiopathic urticaria.
    Desloratadine
  • HY-P99625
    Frexalimab
    		Inhibitor 99.00%
    Frexalimab (SAR441344) is a second-generation monoclonal antibody targeting the CD40 ligand (CD40L) with a good safety profile. Frexalimab inhibits the binding between CD40 and CD40L to modulate immune response. Frexalimab is likely to help prevent the process of β-cell destruction. Frexalimab is proming for multiple sclerosis, lupus erythematosus, Sj gren’s syndrome and type I diabetes research.
    Frexalimab
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. 
 

TNF Receptor Isoform Comparison

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