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-N10454
    Sinulatumolin C
    		Inhibitor
    Sinulatumolin C (compound 3) is an anti-inflammatory agent. Sinulatumolin C has significant TNF-α inhibitory activity with an IC50 value of 2.6 μM.
    Sinulatumolin C
  • HY-P2612
    WP9QY
    		Antagonist
    WP9QY, TNF-a Antagonist, TNF-a Antagonist is a biological active peptide. (This cyclic peptide is designed to mimic the most critical tumor necrosis factor (TNF) recognition loop on TNF receptor I. It prevents interactions of TNF with its receptor. This TNF antagonist is a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.)
    WP9QY
  • HY-N7699A
    D-Trimannuronic acid
    		Activator
    D-Trimannuronic acid, an alginate oligomer is extracted from seaweed. D-Trimannuronic acid can induce TNF‐α secretion by mouse macrophage cell lines. D-Trimannuronic acid can be used for the research of pain and vascular dementia.
    D-Trimannuronic acid
  • HY-N6607R
    Tryptanthrin (Standard)
    		Modulator
    Tryptanthrin (Standard) is the analytical standard of Tryptanthrin. This product is intended for research and analytical applications. Tryptanthrin is an indole quinazoline that could be an alkaloid from indigo-bearing plants. Tryptanthrin is a potent and orally active cellular Leukotriene (LT) biosynthesis inhibitor. Tryptanthrin has anticancer activity. Tryptanthrin suppresses the expression levels of NOS1, COX-2, and NF-κB and regulates the expression levels of IL-2, IL-10, and TNF-α.
    Tryptanthrin (Standard)
  • HY-160433
    TNF-α-IN-12
    		Inhibitor
    TNF-α-IN-12 is a TNF-α inhibitor with IC50 of 0.1 μM. TNF-α-IN-12 can decrease the TNF-α blood levels.
    TNF-α-IN-12
  • HY-N10009
    Cudraflavone B
    		Inhibitor
    Cudraflavone B is a prenylated flavonoid with anti-inflammatory and anti-tumor properties. Cudraflavone B is also a dual inhibitor of COX-1 and COX-2. Cudraflavone B blocks the translocation of nuclear factor κB (NF-κB) from the cytoplasm to the nucleus in macrophages. Thus, Cudraflavone B inhibits tumor necrosis factor α (TNFα) gene expression and secretion. Cudraflavone B also triggers the mitochondrial apoptotic pathway, activates NF-κB, the MAPK p38, and ERK, and induced the expression of SIRT1. Thus Cudraflavone B inhibits the growth of human oral squamous cell carcinoma cells.
    Cudraflavone B
  • HY-111326
    Naphazoline
    		Inhibitor
    Naphazoline (Naphthazoline) is a potent α-adrenergic receptor agonist. Naphazoline reduces vascular hyperpermeability and promotes vasoconstriction. Naphazoline reduces the levels of inflammatory factors (TNF-α, IL-1β and IL-6), cytokines (IFN-γ and IL-4), IgE, GMCSF, and NGF。Naphazoline can be used for non-bacterial conjunctivitis research.
    Naphazoline
  • HY-N9000
    Loganic acid 6′-O-β-D-glucoside
    Loganic acid 6′-O-β-D-glucoside, a iridoidal glucoside, is isolated from the whole plant of Gentiana rhodantha (Gentianaceae). Loganic acid 6′-O-β-D-glucoside inhibits LPS-induced NO and TNF-α production in macrophage RAW264.7 cells.
    Loganic acid 6′-O-β-D-glucoside
  • HY-149496
    Akt/NF-κB/MAPK-IN-1
    		Inhibitor
    Akt/NF-κB/MAPK-IN-1 (compound 2m) is a potent and orally active inhibitor against NO (IC50=7.70 μM) with no significant toxicity. Akt/NF-κB/MAPK-IN-1 shows anti-inflammatory activity by inhibiting Akt/NF-κB and MAPK signaling pathways.
    Akt/NF-κB/MAPK-IN-1
  • 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-N1195
    Sugiol
    		Inhibitor
    Sugiol is an abietane diterpenoid, can be isolated from Calocedrus formosana bark. Sugiol has anti-inflammatory activity, could effectively reduce intracellular reactive oxygen species (ROS) production in lipopolysaccharide (LPS)-stimulated macrophages.
    Sugiol
  • 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-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-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-P3585
    Epobis
    		Inhibitor 99.34%
    Epobis, a dendrimeric peptide, is a recombinant form of erythropoietin. Epobis is a potent erythropoietin receptor agonist. Epobis promotes neuritogenesis in primary motoneurons. Epobis decrease TNF release and crosses the blood-brain barrier. Epobis has anti-inflammatory and memory enhancing properties.
    Epobis
  • 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
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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