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-147836
    Akt/NF-κB/JNK-IN-1
    		Inhibitor
    Akt/NF-κB/JNK-IN-1 (Compound 2i) is an inhibitor of Akt, NF-κB and JNK signaling pathways. Akt/NF-κB/JNK-IN-1 inhibits nitric oxide production with an IC50 of 3.15 μM. Akt/NF-κB/JNK-IN-1 shows anti-inflammatory activities.
    Akt/NF-κB/JNK-IN-1
  • HY-129144
    Dihydrodehydrodiconiferyl alcohol
    Dihydrodehydrodiconiferyl alcohol (compound 2) is a kind of neolignan. Dihydrodehydrodiconiferyl alcohol can be isolated from Anogeissus acuminata. Dihydrodehydrodiconiferyl alcohol has specific cytotoxic activity on melanoma cancer cell line.
    Dihydrodehydrodiconiferyl alcohol
  • HY-111326AR
    Naphazoline nitrate (Standard)
    		Inhibitor
    Naphazoline (nitrate) (Standard) is the analytical standard of Naphazoline (nitrate). This product is intended for research and analytical applications. Naphazoline (Naphthazoline) nitrate is an α-adrenergic receptor agonist. Naphazoline nitrate reduces vascular hyperpermeability and promotes vasoconstriction. Naphazoline nitrate reduces the levels of inflammatory factors (TNF-α, IL-1β and IL-6), cytokines (IFN-γ and IL-4), IgE, GMCSF, and NGF. Naphazoline nitrate can be used for non-bacterial conjunctivitis research.
    Naphazoline nitrate (Standard)
  • 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-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-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-117569
    KF24345 free base
    		Inhibitor
    KF24345 free base is an orally active adenosine uptake inhibitor. KF24345 free base inhibits adenosine uptake by human, mouse, rabbit and hamster erythrocytes with IC50 values ??of 59.5, 130.1, 104.2 and 30.9 nM, respectively. KF24345 free base has anti-inflammatory activity and can inhibit LPS-induced TNF-α production and leukopenia in mice.
    KF24345 free base
  • 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-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-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-156431
    Anti-inflammatory agent 61
    		Inhibitor
    Anti-inflammatory agent 61 (Compound 5b) is a potent anti-inflammatory agent. Anti-inflammatory agent 61 reduces TNF-α expression in LPS-induced inflammation in RAW 264.7 cells. Anti-inflammatory agent 61 alleviates APAP-induced inflammation in HepG2 cells.
    Anti-inflammatory agent 61
  • HY-N12116
    Maceneolignan A
    		Inhibitor
    Maceneolignan A is a natural product that can be isolated from mace, the aril of Myristica fragrans (Myristicaceae). Maceneolignan A inhibits the release of β-hexosaminidase in RBL-2H3 cells, with an IC50 of 48.4 μM. Maceneolignan A inhibits the release of TNF-α in antigen stimulated RBL-2H3 cells, with an IC50 of 63.7 μM.
    Maceneolignan A
  • HY-15643
    LY 303511
    		Activator
    LY303511 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
  • HY-110343
    DBM 1285 dihydrochloride
    		Inhibitor
    DBM 1285 dihydrochloride is an orally active TNF-α production inhibitor with anti-inflammatory effects. DBM 1285 dihydrochloride inhibits Lipopolysaccharide (LPS)-induced TNF-α secretion in various cells of macrophage/monocyte lineage.
    DBM 1285 dihydrochloride
  • HY-12085R
    Apremilast (Standard)
    		Inhibitor
    Apremilast (Standard) is the analytical standard of Apremilast. This product is intended for research and analytical applications. 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 (Standard)
  • HY-118734
    IK-862
    		Inhibitor
    IK-862 is a selective inhibitor of TACE.
    IK-862
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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