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-15790R
    Elobixibat (Standard)
    		Inhibitor
    Elobixibat (Standard) is the analytical standard of Elobixibat. This product is intended for research and analytical applications. Elobixibat is a potent ileal bile acid transporter (IBAT) inhibitor with IC50 values of 0.53 ± 0.17 nM, 0.13 ± 0.03 nM, and 5.8 ± 1.6 nM for human IBAT, mouse IBAT, and canine IBAT.
    Elobixibat (Standard)
  • HY-P9980A
    Belantamab (FUT-8 KO)
    Belantamab (FUT-8 KO) is an anti-BCMA (TNFRSF17) monoclonal antibody expressed by CHO cells with the fucosyltransferase 8 gene (FUT8) knocked out. Fucose deficiency enhances the ADCC effect of the antibody. Belantamab (FUT-8 KO) can be used to synthesize antibody-active molecule conjugate (ADC), Belantamab mafodotin.
    Belantamab (FUT-8 KO)
  • HY-N0182S3
    Fisetin-d5
    		Inhibitor
    Fisetin-d5 is a deuterated labeled Fisetin. Fisetin is a natural flavonol found in many fruits and vegetables with various benefits, such as antioxidant, anticancer, neuroprotection effects.
    Fisetin-d<sub>5</sub>
  • HY-110051
    DPP4-In hydrochloride
    DPP4-In (hydrochloride) is an inhibitor of dipeptidyl peptidase 4 (DPP4) that can reduce DPP4 expression.
    DPP4-In hydrochloride
  • HY-114360AS1
    Taurohyodeoxycholic acid-d4 sodium
    		Inhibitor
    Taurohyodeoxycholic acid-d4 (sodium) is a deuterated labeled Taurohyodeoxycholic acid (sodium). 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-d<sub>4</sub> sodium
  • HY-N4100R
    Trilobatin (Standard)
    Trilobatin (Standard) is the analytical standard of Trilobatin. This product is intended for research and analytical applications. 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 (Standard)
  • HY-12085S1
    Apremilast-d8
    		Inhibitor
    Apremilast-d8 (CC-10004-d8) is deuterium labeled Apremilast. 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-d<sub>8</sub>
  • HY-N3541
    Cardenolide B-1
    		Inhibitor
    Cardenolide B-1 is a Steroids product that can be isolated from the herbs of Nerium oleander.
    Cardenolide B-1
  • HY-P991052
    GSK-3174998
    		Inhibitor
    GSK-3174998 is a humanized IgG1 OX40/TNFRSF4 agonistic monoclonal antibody. GSK-3174998 has the potential for the study of advanced solid tumors. The isotype control for GSK-3174998 can refer to Human IgG1 kappa, Isotype Control (HY-P99001).
    GSK-3174998
  • HY-107632G
    GYY4137 (GMP)
    		Inhibitor
    GYY4137 (GMP) is the GMP-grade version of GYY4137 (HY-107632). Small molecules of GMP grade can be used as adjuvant reagents in cell therapy. GYY4137 (GMP) is a sustained-release H2S donor possessing vasodilatory, antihypertensive, and anti-inflammatory activities. GYY4137 (GMP) can inhibit cell growth, induce apoptosis, and cause cell cycle arrest by blocking the STAT3 pathway, demonstrating potent anticancer activity.
    GYY4137 (GMP)
  • HY-20070
    BMS-566394
    		Inhibitor
    BMS-566394 is a potent inhibitor of tumor necrosis factor-α (TNF-α) converting enzyme (TACE) that helps reduce the production of TNF-α, thereby alleviating inflammation and immune-mediated diseases and can be used in the study of inflammatory and autoimmune diseases.
    BMS-566394
  • HY-N1125
    Triptobenzene H
    		Inhibitor
    Triptobenzene H (Hypoglic acid) significantly increases TNF-α and IL-1β mRNA levels in macrophages, causing indirect liver damage.
    Triptobenzene H
  • HY-N13184
    Giraldoid B
    		Inhibitor
    Giraldoid B is an active ingredient that can be isolated from Girald Daphne Bark. Giraldoid B can inhibit LPS induced NO and b>TNF-α production in RAW264.7 and has anti-inflammatory activity.
    Giraldoid B
  • HY-N11994
    Aloeresin G
    		Inhibitor
    Aloeresin G is a chromone glycoside that can be isolated from Aloe. Aloeresin G has a weak inhibitory effect on TNFα-induced NF-κB transcriptional activity, with an IC 50 value of 40.02 μM.
    Aloeresin G
  • HY-121200
    Azadirone
    		Inducer
    Azadirone sensitized cancer cells to TNF-related apoptosis-inducing ligand (TRAIL) through ROS-ERK-CHOP-mediated up-regulation of DR5 and DR4 expression, down-regulation of cell survival proteins, and up-regulation of proapoptotic proteins (Bid). Azadirone has antiplasmodial activity.
    Azadirone
  • HY-158650
    10-OAHSA
    		Inhibitor
    10-OAHSA is one of fatty acid esters of hydroxy fatty acids (FAHFAs). 10-POHSA increases glucose-stimulated insulin secretion (GSIS) at a high glucose concentration. 10-OAHSA reduces LPS (HY-D1056)-induced Tnf-α secretion in bone marrow-derived dendritic cells (BMDCs).
    10-OAHSA
  • HY-N0619R
    Mulberroside A (Standard)
    		Inhibitor
    Mulberroside A (Standard) is the analytical standard of Mulberroside A. This product is intended for research and analytical applications. Mulberroside A is one of the main bioactive constituent in mulberry (Morus alba L.). Mulberroside A decreases the expressions of TNF-α, IL-1β, and IL-6 and inhibits the activation of NALP3, caspase-1, and NF-κB and the phosphorylation of ERK, JNK, and p38, exhibiting anti-inflammatory antiapoptotic effects. Mulberroside A shows inhibitory activity against mushroom tyrosinase with an IC50 of 53.6 μM.
    Mulberroside A (Standard)
  • HY-116426
    IDT
    		Modulator
    IDT is a safe and effective TNFα and innate immune system modulator. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation and increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT can be used in Alzheimer's disease research.
    IDT
  • HY-B0809S1
    Theophylline-d3
    		Inhibitor
    Theophylline-d3 is deuterated labeled Theophylline (HY-B0809). 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-d<sub>3</sub>
  • HY-P991194
    HFB-200301
    		Ligand
    HFB-200301 is an IgG1 antibody targeting tumor necrosis factor receptor 2 (TNFR2). HFB-200301 promotes the activation of TNFR2, thereby activating relevant signaling pathways, such as activating RelA and cRel-containing NF-κB dimers through the classical NF-κB pathway, affecting cell metabolism and gene expression in the presence of sTNF. HFB-200301 is promising for research of cancers.
    HFB-200301
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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