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-176554
    sEH-IN-21
    		Inhibitor
    sEH-IN-21 is an orally active sEH inhibitor with IC50s of 0.1 nM for hsEH and msEH. sEH-IN-21 potently inhibits NF-κB signaling pathways. sEH-IN-21 shows a strong anti-inflammatory activity, decreases the release of IL-6 and TNF-α and maintained the integrity of the intestinal barrier. sEH-IN-21 can be used for the study of inflammatory bowel disease (IBD).
    sEH-IN-21
  • HY-N10448
    Sinulatumolin E
    		Inhibitor
    Sinulatumolin E (compound 6), a terpenoid, displays significant TNF-α inhibitory activity with an IC50 of 3.6 μM. Sinulatumolin E (compound 6) exhibits anti-inflammatory activity.
    Sinulatumolin E
  • HY-P991120
    Balertatug
    		Inhibitor
    Balertatug is a human IgG1K antibody targeting CD70. The corresponding isotype control is: Human lgG1 kappa, lsotype Control (HY-P99001).
    Balertatug
  • HY-P11093
    Papiliocin
    		Inhibitor
    Papiliocin is a potent peptide antibiotic with both anti-inflammatory and antibacterial activities. Papiliocin is primarily active against Gram-negative bacteria. Papiliocin exhibits strong anti-inflammatory activity against cell, exerting its anti-inflammatory activity by inhibiting the production of NO and the secretion of TNF-α and MIP-2. Papiliocin participates in the innate defense response mechanism by inhibiting the Toll-like receptor pathway and NF-κB. Papiliocin induces apoptosis in fungal cells and increases the total level of intracellular ROS. Papiliocin acts as an effective antiseptic peptide in sepsis models. Papiliocin is useful in anti-inflammatory and antibacterial research.
    Papiliocin
  • HY-P11002
    PTD
    		Control
    PTD (Antennapedia leader peptide) is a negative control of TRAF6 inhibitor peptide DRQIKIWFQNRRMKWKK-RKIPTEDEY.
    PTD
  • HY-175833
    NF-κB-IN-20
    		Inhibitor
    NF-κB-IN-20 is an orally active NF-κB inhibitor. NF-κB-IN-20 directly binds to the Keap1 protein, activating the Keap1/Nrf2/HO-1 antioxidant pathway, and simultaneously inhibiting the NF-κB inflammatory pathway, thereby synergistically reducing oxidative stress and inflammatory responses. NF-κB-IN-20 M11 inhibits the expression of IL-6, IL-1β, and TNF-α, significantly reduces the level of ROS, and restores the mitochondrial membrane potential. NF-κB-IN-20 can be used for the study of acute lung injury (ALI).
    NF-κB-IN-20
  • HY-P99753
    Nerelimomab
    		Inhibitor
    Nerelimomab (BAYX1351) is an anti-TNF-α antibody. Nerelimomab can be used for research of sepsis.
    Nerelimomab
  • HY-175007
    RIPK1-IN-32
    		Inhibitor
    RIPK1-IN-32 is a RIPK inhibitor with anti-inflammatory activity. RIPK1-IN-32 inhibits nitric oxide (NO) release with an IC50 of 3.26 μM. RIPK1-IN-32 significantly alleviates acute liver injury associated with sepsis through the RIPK1/NF-κB/MAPK pathway, therefore preventing the nuclear translocation of p65 and c-fos, which results in reduced expression of TNF-α and IL-6. RIPK1-IN-32 can be used for the study of acute liver injury and sepsis.
    RIPK1-IN-32
  • 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-W015490R
    1,4-Naphthoquinone (Standard)
    		Inhibitor
    1,4-Naphthoquinone is an inhibitor with broad-spectrum inhibitory activity targeting DNA polymerase, NF-κB and monoamine oxidase (MAO-A/B), with antibacterial and anti-biofilm efficacy. 1,4-Naphthoquinone is a competitive inhibitor of MAO-B (Ki=1.4 μM) and a non-competitive inhibitor of MAO-A (Ki=7.7 μM). 1,4-Naphthoquinone inhibits DNA polymerase pol α, β, γ, δ, ε, λ with IC50 ranging from 5.57-128 μM. 1,4-Naphthoquinone inhibits tumor cell proliferation, induces apoptosis and necrosis, and has anti-angiogenic and anti-inflammatory activities by inducing oxidative stress, depleting glutathione (GSH), inhibiting DNA polymerase-mediated DNA synthesis and blocking NF-κB nuclear translocation. 1,4-Naphthoquinone can be used in anti-bacterial , anti-tumor and anti-inflammatory studies, including inhibition of melanoma and colon cancer cell growth and endothelial cell function, as well as LPS-induced inflammation models.
    1,4-Naphthoquinone (Standard)
  • HY-N15307
    Trigraecum
    		Inhibitor
    Trigraecum is a flavonoid compound found in Dracaena steudneri and Dalbergia cochinchinensis, exhibiting anti-inflammatory activity. It can inhibit the LPS (HY-D1056)-induced production of IL-1β, IL-2, GM-CSF, and TNF-α in human peripheral blood mononuclear cells. Trigraecum holds promise for research on inflammatory diseases.
    Trigraecum
  • 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-N1965R
    Gaultherin (Standard)
    		Inhibitor
    Gaultherin (Standard) is the analytical standard for Gaultherin (HY-N1965). Gaultherin is an orally active non-steroidal anti-inflammatory agent. Gaultherin selectively inhibits NF-κB, MAPK, COX-2 (IC50 = 0.35 mg/mL), LOX (IC50 = 0.56 mg/mL) and HYAL (IC50 = 28.58 μg/mL) to exert anti-inflammatory, antipyretic and analgesic effects. Gaultherin exhibits modest direct antioxidant capacity, greater in cell-based models. Gaultherin does not affect COX-1 so that avoids the common gastrointestinal side effects of Aspirin (HY-14654).
    Gaultherin (Standard)
  • HY-128776
    Antitumor agent-19
    		Activator
    Antitumor agent-19 is an antitumor agent that targets tumor-associated macrophages (TAMs) and can be used as a potent TAMs modulator. Antitumor agent-19 can increase TNF-alpha levels in tumor cells with EC50 values???of 17.18 μM and 18.87 μM in RAW 264.7 cells and BMDM cells, respectively.
    Antitumor agent-19
  • HY-N0136R
    Taxifolin (Standard)
    Taxifolin (Standard) is the analytical standard of Taxifolin. This product is intended for research and analytical applications. 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 (Standard)
  • HY-N3021R
    D-chiro-Inositol (Standard)
    		Inhibitor
    D-chiro-Inositol is a stereoisomer of inositol that exhibits activities such as improving glucose metabolism, anti-tumor effects, anti-inflammatory properties, and antioxidant activity. D-chiro-Inositol effectively alleviates cholestasis by enhancing bile acid secretion and reducing oxidative stress. D-chiro-Inositol improves insulin resistance, lowers hyperglycemia and circulating insulin levels, reduces serum androgen levels, and ameliorates some metabolic abnormalities associated with X syndrome by mimicking the action of insulin. Additionally, D-chiro-Inositol can induce a reduction in pro-inflammatory factors (such as Nf-κB) and cytokines (such as TNF-α), thereby exerting anti-inflammatory effects. D-chiro-Inositol may be used in the study of liver cirrhosis, breast cancer, type 2 diabetes, and polycystic ovary syndrome.
    D-chiro-Inositol (Standard)
  • HY-N13869
    Asperlin
    		Inhibitor
    Asperlin is an orally active marine-derived antibiotic with antifungal, anticancer, anti-inflammatory and anti-atherosclerotic activities. Asperlin induces apoptosis. Asperlin increases reactive oxygen species (ROS)- and DNA damage-associated G2/M phase arrest and ATM phosphorylation. Asperlin is effective in preventing HFD-induced obesity and modulating gut microbiota.
    Asperlin
  • 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-N0724R
    Mesaconitine (Standard)
    		Inhibitor
    Mesaconitine (Standard) is the analytical standard of Mesaconitine. This product is intended for research and analytical applications.
    Mesaconitine (Standard)
  • HY-113402AR
    Gamma-glutamylcysteine TFA (Standard)
    		Inhibitor
    Gamma-glutamylcysteine (TFA) (Standard) is the analytical standard of Gamma-glutamylcysteine (TFA). This product is intended for research and analytical applications. Gamma-glutamylcysteine (γ-Glutamylcysteine) TFA, an intermediate in glutathione (GSH) synthesis, is a dipeptide served as an essential cofactor for the antioxidant enzyme glutathione peroxidase (GPx). Gamma-glutamylcysteine TFA also upregulates the level of the anti-inflammatory cytokine IL-10 and reduces the levels of the pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). Gamma-glutamylcysteine TFA attenuates the changes in metalloproteinase activity in oligomeric Aβ40-treated astrocytes.
    Gamma-glutamylcysteine TFA (Standard)
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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