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-N3602A
    rel-Cleroindicin F
    		Inhibitor
    rel-Cleroindicin F (Rengyolone) is a cyclohexyl acetyl compound that can be isolated from the fruit of forsythia and has anti-inflammatory activity. It strongly inhibits the production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α). rel-Cleroindicin F does this by downregulating the activity of NF-κB and NF-κB kinases in RAW 264.7 cells stimulated by LPS (HY-D1056), thus inhibiting the expression of inducible nitric oxide synthase (NO Synthase) and nitric oxide production.
    rel-Cleroindicin F
  • HY-N1949R
    Homoplantaginin (Standard)
    		Inhibitor
    Homoplantaginin (Standard) is the analytical standard of Homoplantaginin. This product is intended for research and analytical applications. Homoplantaginin is a flavonoid from a traditional Chinese medicine Salvia plebeia with antiinflammatory and antioxidant properties. Homoplantaginin could inhibit TNF-α and IL-6 mRNA expression, IKKβ and NF-κB phosphorylation.
    Homoplantaginin (Standard)
  • HY-144368
    CO delivery molecule 1
    		Inhibitor
    CO delivery molecule 1 (compound 4) localizes to the endoplasmic reticulum, mitochondria, and lysosomes. Subcellular localization of CO delivery molecule 1 results in CO-induced toxicity effects. Anti-inflammatory effects of CO delivery molecule 1, as measured by TNF-α suppression, occur at the nanomolar level in the absence of CO release, and are enhanced with visible-light-induced CO release.
    CO delivery molecule 1
  • HY-N0722R
    Neochlorogenic acid (Standard)
    		Inhibitor
    Neochlorogenic acid (Standard) is the analytical standard of Neochlorogenic acid. This product is intended for research and analytical applications. Neochlorogenic acid is a natural polyphenolic compound found in dried fruits and other plants. Neochlorogenic acid inhibits the production of TNF-α and IL-1β. Neochlorogenic acid suppresses iNOS and COX-2 protein expression. Neochlorogenic acid also inhibits phosphorylated NF-κB p65 and p38 MAPK activation.
    Neochlorogenic acid (Standard)
  • HY-12085S3
    Apremilast-d3
    		Inhibitor
    Apremilast-d3 (CC-10004-d3) 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>3</sub>
  • HY-147950
    PDE4-IN-10
    		Inhibitor
    PDE4-IN-10 (compound 7a) is a potent PDE4 inhibitor, with an IC50 of 7.01 μM for PDE4B. PDE4-IN-10 shows selectivity, microsomal stability, inhibition of TNF-α and no major toxicities in vitro.
    PDE4-IN-10
  • HY-N0358R
    1,4-Dicaffeoylquinic acid (Standard)
    		Inhibitor
    1,4-Dicaffeoylquinic acid (Standard) is the analytical standard of 1,4-Dicaffeoylquinic acid. This product is intended for research and analytical applications. 1,4-Dicaffeoylquinic acid (1,4-DCQA) is a phenylpropanoid from Xanthii fructus, inhibits LPS-stimulated TNF-α production.
    1,4-Dicaffeoylquinic acid (Standard)
  • HY-N10453
    Sinulatumolin D
    Sinulatumolin D (compound 4) is an anti-inflammatory agent. Sinulatumolin D has significant TNF-α inhibitory activity with an IC50 value of 5.5 μM.
    Sinulatumolin D
  • HY-155027
    DPP-4-IN-8
    		Inhibitor
    DPP-4-IN-8 (compound 27) is a potent and selective DPP4 (dipeptidyl peptidase 4) inhibitor, with a Ki of 0.96 μM. DPP-4-IN-8 blocks the dipeptidase activity of DPP4 in both Caco-2 and HepG-2 cells. DPP-4-IN-8 also dose-dependently suppresses the expression levels of the chemokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β).
    DPP-4-IN-8
  • HY-163035
    EM-163
    		Inhibitor
    EM-163 is a summative BB-Loop analog. EM-163 can alleviate inflammation and prevent death from toxic shock by targeting the TIR domain of MyD88. EM-163 can be used in the study of SEB poisoning (SEB: Staphylococcal enterotoxin B).
    EM-163
  • 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-P99753
    Nerelimomab
    		Inhibitor
    Nerelimomab (BAYX1351) is an anti-TNF-α antibody. Nerelimomab can be used for research of sepsis.
    Nerelimomab
  • HY-P10399
    KGYY15
    		Inhibitor
    KGYY15 (Mouse KGYY15) is a CD40 targeting peptide, which weakly inhibits the CD40-CD40L interaction with IC50 of more than 1mM. KGYY15 activates 33% NF-κB pathway at 100 μM.
    KGYY15
  • 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-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-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-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)
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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