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-N6739R
    Beauvericin (Standard)
    Doxycycline (monohydrate) (Standard) is the analytical standard of Doxycycline (monohydrate). This product is intended for research and analytical applications. Doxycycline monohydrate is an antibiotic and broad-spectrum metalloproteinase (MMP) inhibitor.
    Beauvericin (Standard)
  • HY-160436
    TNF-α-IN-15
    		Inhibitor
    TNF-α-IN-15 is a TNF-α inhibitor. TNF-α-IN-15 can decrease the TNF-α blood levels.
    TNF-α-IN-15
  • HY-N9867
    Gnetifolin E
    		Inhibitor
    Gnetifolin E is a resveratrol trimer derivative that can be isolated from Gnetum brunonianum. Gnetifolin E has anti-inflammatory activity, and inhibits TNF-α.
    Gnetifolin E
  • HY-114592
    M199
    		Activator
    M199 is a potent TLR3/TLR9 signaling inhibitor. M199 induces secretion of IL-6, IL-8 and TNFα in human PBMCs. M199 is used as a selective inducer of the immune response.
    M199
  • HY-153329
    TNF-α-IN-9
    		Inhibitor
    TNF-α-IN-9 (compound 48) is a analog of NDM-1 inhibitor-3 (HY-150758). TNF-α-IN-9 is a TNF-α inhibitor. TNF-α-IN-9 shows low inhibitory activity.
    TNF-α-IN-9
  • HY-153952
    Immuno modulator-1
    		Inhibitor
    Immuno modulator-1 (compound 22) inhibits TNFα and IL-2 secretion in human peripheral blood mononuclear cells (hPBMC), with IC50 values of 4.7 and 26 nM, respectively. Immuno modulator-1 shows hERG potassium channel blocking effect, with Inhibitory percentage of 20% at 3 μM.
    Immuno modulator-1
  • HY-161821
    Antitumor agent-173
    		Control
    Antitumor agent-173 (Compound 4b) is a prodrug of Cycloicaritin (HY-N1940). Antitumor agent-173 is a substrate for OATP2B1. Antitumor agent-173 selectively inhibits the growth of tumor Antitumor agent-173 significantly increases the oral bioavailability of Cycloicaritin and exerts good antitumor activity and safety.
    Antitumor agent-173
  • HY-P991070
    ADG-106
    		Agonist
    ADG-106 is a fully human agonistic monoclonal IgG4 antibody against CD137 (4-1BB). ADG-106 has the mechanism to activate CD137 via strong FcγRIIB-mediated crosslinking while antagonizing CD137 ligands. The isotype control for ADG-106 can refer to Human IgG4 (S228P) kappa, Isotype Control (HY-P99003).
    ADG-106
  • HY-N0822R
    Shikonin (Standard)
    		Inhibitor
    Shikonin (Standard) is the analytical standard of Shikonin. This product is intended for research and analytical applications. Shikonin is a major component of a Chinese herbal medicine named zicao. Shikonin is a potent TMEM16A chloride channel inhibitor with an IC50 of 6.5 μM. Shikonin is a specific pyruvate kinase M2 (PKM2) inhibitor and can also inhibit TNF-α and NF-κB pathway. Shikonin decreases exosome secretion through the inhibition of glycolysis. Shikonin inhibits AIM2 inflammasome activation.
    Shikonin (Standard)
  • HY-128754R
    Monoolein (Standard)
    		Inhibitor
    Monoolein is a biocompatible lipid molecule that can be used as a carrier for bone repair. Monoolein exhibits anti-inflammatory activity by inhibiting the immune response induced by LPS (HY-D1056). It exerts its anti-inflammatory effects by reducing the production of immune response factors such as IL-12 p40, IL-6, and TNF-α, and inhibiting the generation of NO. Monoolein can be used in drug delivery and research in the field of inflammatory diseases .
    Monoolein (Standard)
  • 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-163162
    Anhydro-Ouabain
    		Inhibitor
    Anhydro-Ouabain (compound 20) is a cardiotonic steroid which shows anti-inflammatory and neuroprotective activities and thus can be used in neurological research.
    Anhydro-Ouabain
  • HY-115577
    Mitochonic acid 35
    		Inhibitor
    Mitochonic acid 35 is an IAA analogue with cytoprotective effects.
    Mitochonic acid 35
  • 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-P99893
    Rozibafusp alfa
    		Inhibitor
    Rozibafusp alfa (AMG-570) is a humanized IgG2-κ monoclonal antibody targets ICOSL and BAFF. Prezalumab demonstrates beneficial activities on the arthritis of systemic lupus erythematosus. Prezalumab can be used for the research of sjogren's syndrome cutaneous lupus erythematosus, psoriasis and systemic lupus erythematosus (SLE).
    Rozibafusp alfa
  • 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 99.74%
    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
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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