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-107737
    1,2-DLPC
    		Activator ≥98.0%
    1,2-DLPC (1,2-Dilauroyl-sn-glycero-3-phosphocholine) is a ligand for LRH-1 agonists. 1,2-DLPC is a phospholipid used in the synthesis of liposomes. 1,2-DLPC enhances fat breakdown and apoptosis in fat cells through a TNFα-dependent pathway, while also inhibiting palmitate-induced insulin resistance through PPARα-mediated inflammation in muscle cells.
    1,2-DLPC
  • HY-P99909
    Elranatamab
    		99.962%
    Elranatamab (PF-06863135) is an anti-CD3E/TNFRSF17 human IgG2κ monoclonal antibody. Recommend Isotype Controls: Human IgG2 kappa, Isotype Control (HY-P99002).
    Elranatamab
  • HY-P99796
    Ozoralizumab
    		Inhibitor 99.80%
    Ozoralizumab (ATN-103) is an anti-TNFα humanized antibody. Ozoralizumab is a humanized trivalent nanobody compound that consists of two anti-human TNFα nanobodies and an anti-human serum albumin (HSA) nanobody. Ozoralizumab can be used in research of arthritis.
    Ozoralizumab
  • HY-N0448
    10-Gingerol
    		Inhibitor 99.34%
    10-Gingerol is an AMPK agonist, which is found in the ginger oleoresin from fresh rhizome with anti-inflammatory, antioxidant and anti-proliferative activities. 10-Gingerol suppresses neointimal hyperplasia and inhibits vascular smooth muscle cell proliferation. 10-Gingerol exhibits substantial scavenging activities with an IC50 value of 10.47 μM against DPPH radical, an IC50 value of 1.68 μM against superoxide radical and an IC50 value of 1.35 μM against hydroxyl radical. 10-Gingerol inhibits the proliferation of MDA-MB-231 tumor cell line with an IC50 of 12.1 μM. 10-Gingerol suppresses the proliferation, migration, invasion, and induced apoptosis through targeting the PI3K/Akt signaling pathway in MDA-MB-231/IR cells. 10-Gingerol is promising for research of ulcerative colitis.
    10-Gingerol
  • HY-142618
    TNF-α-IN-6
    		Inhibitor 99.55%
    TNF-α-IN-6 (compound 12) is an orally effective allosteric inhibitor of TNFα (KD = 6.8 nM). TNF-α-IN-6 has anti-inflammatory effects.
    TNF-α-IN-6
  • HY-114360
    Taurohyodeoxycholic acid
    		Inhibitor 99.73%
    Taurohyodeoxycholic acid is an orally active 6 alpha-hydroxylated bile acid. Taurohyodeoxycholic acid decreases colonic MPO activity, TNF-α, lL-6 serum levels and the expression of COX-2. Taurohyodeoxycholic acid alleviates trinitrobenzene sulfonic acid induced ulcerative colitis via regulating Th1/Th2 and Th17/Treg cells balance. Taurohyodeoxycholic acid ameliorates high-fat diet-induced nonalcoholic fatty liver disease in mice. Taurohyodeoxycholic acid prevents Taurochenodeoxycholic acid (HY-N2027)-induced hepatotoxicity in bile fistula rats. Taurohyodeoxycholic acid can be used for the study of nonalcoholic fatty liver disease (NAFLD), colitis and biliary fistula.
    Taurohyodeoxycholic acid
  • HY-P99653
    Ianalumab
    		Inhibitor 99.97%
    Ianalumab (VAY-736) is a human, decarboxylated antibody against BAFF-R. Ianalumab can block the interaction between BAFF and BAFF-R and antagonize the apoptosis protection mediated by BAFF. Ianalumab exerts antibody-dependent cytotoxic (ADCC), depending on effector cell activation mediated by immune receptor tyrosine activation motif (ITAM).
    Ianalumab
  • HY-156454
    UCB-6876
    		Inhibitor 98.49%
    UCB-6876 is a TNFα inhibitor. UCB-6876 can specifically bind to the asymmetric crystalline form of the TNF-α trimer, with a KD of 22 μM.
    UCB-6876
  • HY-147141
    HS-276
    		Inhibitor 98.93%
    HS-276 is an orally active, potent and highly selective TAK1 inhibitor, with a Ki of 2.5 nM. HS-276 shows significant inhibition of TAK1, CLK2, GCK, ULK2, MAP4K5, IRAK1, NUAK, CSNK1G2, CAMKKβ-1, and MLK1, with IC50 values of 8.25, 29, 33, 63, 125, 264, 270, 810, 1280, and 5585 nM, respectively. HS-276 can be used for rheumatoid arthritis (RA) research.
    HS-276
  • HY-B1201
    Tiratricol
    		Inhibitor 98.88%
    Tiratricol is an orally available thyroid hormone analog that inhibits pituitary thyroid-stimulating hormone secretion. Tiratricol is an intracellular toxin neutralizer that inhibits LPS and lipid A cytotoxicity with IC50s of 20 μM and 32 μM, respectively. Tiratricol reduces TNF production in lipopolysaccharide-stimulated macrophages. Tiratricol also has antiviral activity and is an inhibitor of yellow fever virus (Flavivirus). It can bind to the RdRp domain of the viral NS5 protein to hinder YFV replication..
    Tiratricol
  • HY-N0042
    Ginsenoside Rc
    		Inhibitor ≥98.0%
    Ginsenoside Rc, one of major Ginsenosides from Panax ginseng, enhances GABA receptorA (GABAA)-mediated ion channel currents (IGABA). Ginsenoside Rc inhibits the expression of TNF-α and IL-1β.
    Ginsenoside Rc
  • HY-N0368
    Linalool
    		99.11%
    Linalool is a natural monoterpene which is a competitive NMDA receptor antagonist. Linalool is orally active and crosses the blood-brain barrier. Linalool has anticancer, antibacterial, anti-inflammatory, neuroprotective, anxiolytic, antidepressant, anti-stress, cardioprotective, hepatoprotective, nephroprotective and pulmonary protective activities.
    Linalool
  • HY-P99046
    Selicrelumab
    		Agonist
    Selicrelumab is an agonist CD40 antibody, induces changes in the tumor microenvironment. Selicrelumab can be used for the research of pancreatic cance and neoadjuvant study.
    Selicrelumab
  • HY-A0059
    Nifuratel
    		99.93%
    Nifuratel (NF 113) is an orally active broad-spectrum antibiotic with antiprotozoal, antibacterial, anticancer and anti-inflammatory activities, and has good inhibitory effects on Candida and Trichomonas. Nifuratel is also a STAT3 inhibitor, which significantly inhibits the growth and proliferation of human gastric cancer cells and induces apoptosis. In addition, Nifuratel also inhibits mast cell-mediated antigen hypersensitivity reactions and can be used in the study of IgE-mediated allergic diseases.
    Nifuratel
  • HY-N2464
    Maltotetraose
    		99.88%
    Maltotetraose can serve as a substrate for enzyme-linked assays to measure amylase activity in biological fluids. Maltotetraose has oral active, and reduces TNF-α-induced inflammatory responses by inhibiting NF-κB activity and decreasing ICAM-1 expression. Maltotetraose also inhibits PDGF-induced vascular smooth muscle cell migration and neovascularization. Additionally, Maltotetraose derivatives can function as probes for detecting bacterial infections by targeting the maltodextrin transporter. With good long-term safety, Maltotetraose holds promise for research in atherosclerosis-related diseases.
    Maltotetraose
  • HY-134240
    L-Threonic acid magnesium
    		Antagonist ≥99.0%
    L-Threonic acid magnesium (Magnesium L-threonate) is the enantiomer of Threonic acid and the metabolite of vitamin C (HY-B0166). L-Threonic acid magnesium is a magnesium supplementation, that improves the brain magnesium concentration, inhibits the activation of TNF-α/NF-κB signaling pathway. L-Threonic acid magnesium can be used in research of Alzheimer’s disease. L-Threonic acid magnesium is orally active.
    L-Threonic acid magnesium
  • 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-B0679
    Lubiprostone
    		Antagonist 99.09%
    Lubiprostone (SPI-0211) increases intestinal fluid secretion through generation of CIC-2/CFTR and activation of cAMP signaling pathway. Lubiprostone inhibits myeloperoxidase (MPO) activity, downregulates Indomethacin (HY-14397)-induced iNOS and TNFα expression. Lubiprostone can be used for chronic constipation research.
    Lubiprostone
  • HY-110247
    TRAF-STOP inhibitor 6877002
    		Inhibitor 99.67%
    TRAF-STOP inhibitor 6877002 is a selective CD40-TRAF6 interaction inhibitor. TRAF-STOP inhibitor 6877002 exerts anti-atherosclerotic activity by blocking the CD40-TRAF6 signaling pathway, inhibiting classical monocyte activation, leukocyte recruitment, and macrophage activation and migration. TRAF-STOP inhibitor 6877002 reduces the phosphorylation levels of signaling intermediates in the canonical NF-κB pathway.
    TRAF-STOP inhibitor 6877002
  • HY-N0635
    Prim-O-glucosylcimifugin
    		99.94%
    Prim-O-glucosylcimifugin exerts anti-inflammatory effects through the inhibition of iNOS and COX-2 expression by through regulating JAK2/STAT3 signaling.
    Prim-O-glucosylcimifugin
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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