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-N1904
    4′-Hydroxywogonin
    		Inhibitor 98.22%
    4′-Hydroxywogonin (8-Methoxyapigenin), a flavonoid, could be isolated from a variety of plants including Scutellaria barbata and Verbena littoralis. 4′-Hydroxywogonin has anti-inflammatory activity via TAK1/IKK/NF-κB, MAPKs and PI3/AKT signaling pathways. 4′-Hydroxywogonin inhibits angiogenesis by disrupting PI3K/AKT signaling. 4′-Hydroxywogonin inhibits cell proliferation and induces apoptosis.
    4′-Hydroxywogonin
  • HY-124686
    ER-464195-01
    		Inhibitor 99.72%
    ER-464195-01 is an orally active calreticulin (CRT) and integrin α subunits (ITGAs) binding inhibitor. ER-464195-01 inhibits leukocyte infiltration and subsequent inflammatory cascade reactions by dissociating the binding between CRT and ITGA. ER-464195-01 down-regulates the expression of pro-inflammatory genes (such as TNF-α, IL-1β, IL-6, IL-17f) induced by DSS (HY-116282C), and inhibit the phosphorylation of STAT3 and the production of serum amyloid A (SAA). ER-464195-01 can be used for the study of inflammatory bowel disease (IBD).
    ER-464195-01
  • HY-137431A
    (R)-Asundexian
    		Control 99.97%
    (R)-Asundexian ((R)-BAY-2433334) is the enantiomer of Asundexian (HY-137431). (R)-Asundexian can be used in studies of cardiovascular disease (especially thrombotic or thromboembolic disease), edema, and ophthalmic disease.
    (R)-Asundexian
  • HY-P99653A
    Ianalumab (FUT8-KO)
    		Inhibitor
    Ianalumab (FUT8-KO) is an anti-BAFF-R monoclonal antibody expressed by CHO cells with the fucosyltransferase 8 gene (FUT8) knocked out. Fucose deficiency enhances the ADCC effect of the antibody. Ianalumab (FUT8-KO) can block the interaction between BAFF and BAFF-R and antagonize the apoptosis protection mediated by BAFF.
    Ianalumab (FUT8-KO)
  • HY-N0509R
    Astilbin (Standard)
    		Inhibitor
    Astilbin (Standard) is the analytical standard of Astilbin. This product is intended for research and analytical applications. Astilbin is a flavonoid compound and enhances NRF2 activation. Astilbin also suppresses TNF-α expression and NF-κB activation.
    Astilbin (Standard)
  • HY-P3203A
    DSTYSLSSTLTLSK TFA
    		98.44%
    DSTYSLSSTLTLSK TFA is a generic human peptide and can be used for infliximab quantitative detection. Infliximab (Avakine) is a chimeric monoclonal IgG1 antibody that specifically binds to TNF-α.
    DSTYSLSSTLTLSK TFA
  • HY-133807B
    (R)-Benpyrine
    		Control 99.17%
    (R)-Benpyrine is the isomer of Benpyrine (HY-133807), and can be used as an experimental control. Benpyrine is a highly specific and orally active TNF-α inhibitor with a KD value of 82.1 μM. Benpyrine tightly binds to TNF-α and blocks its interaction with TNFR1, with an IC50 value of 0.109 μM. Benpyrine has the potential for TNF-α mediated inflammatory and autoimmune disease research.
    (R)-Benpyrine
  • HY-159886
    MG-C-30
    		Agonist
    MG-C-30 is an orally active agonist for CD27 with an EC50 of 0.84 μM. MG-C-30 activates NK cells and T cell co-stimulatory signals, and enhances immune response. MG-C-30 exhibits antitumor efficacy in mouse EG7-OVA model.
    MG-C-30
  • HY-N3595
    Cleomiscosin A
    		Inhibitor 99.15%
    Cleomiscosin A is a coumarino-lignoid from branch of Macaranga adenantha. Cleomiscosin A is active against TNF-alpha secretion of the mouse peritoneal macrophages.
    Cleomiscosin A
  • HY-N0182A
    Fisetin quarterhydrate
    		Inhibitor 98.64%
    Fisetin quarterhydrate is a natural flavonol found in many fruits and vegetables with various benefits, such as antioxidant, anticancer, neuroprotection effects.
    Fisetin quarterhydrate
  • HY-159884
    MG-T-19
    		Activator
    MG-T-19 is an effective TIM-3 inhibitor that can suppress the interaction of TIM-3 with PtdSer, CEACAM1, and Gal-9. MG-T-19 can increase the production of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in peripheral blood mononuclear cells (PBMCs) from healthy donors, and enhance the ability of PBMCs to inhibit the proliferation of Kasumi-1 cells (an acute myelogenous leukemia cell line).
    MG-T-19
  • HY-117082
    UTL-5g
    		Inhibitor 99.92%
    UTL-5g (GBL-5g), an anti-inflammatory TNF-α inhibitor, has chemoprotective and liver radioprotective effects. UTL-5g lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by Cisplatin through TNF-α inhibition among other factors.
    UTL-5g
  • HY-N8371
    Shizukaol B
    		Inhibitor
    Shizukaol B is a lindenane-type dimeric sesquiterpene, used to be isolated from the whole plant of Chloranthus henryi. Shizukaol B has anti-inflammatory effect against lipopolysaccharide (LPS)-induced activation of BV2 microglial cells. Shizukaol B inhibits iNOS and COX-2, and suppresses NO production, TNF-α, and IL-1β expression.
    Shizukaol B
  • HY-N0569R
    Madecassic acid (Standard)
    		Inhibitor
    Madecassic acid (Standard) is the analytical standard of Madecassic acid. This product is intended for research and analytical applications. Madecassic acid is isolated from Centella asiatica (Umbelliferae). Madecassic acid has anti-inflammatory properties caused by iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 inhibition via the downregulation of NF-κB activation in RAW 264.7 macrophage cells.
    Madecassic acid (Standard)
  • HY-154821
    DRI-C21041
    		Inhibitor
    DRI-C21041 is a CD40/CD40L interaction inhibitor, with an IC50 of 0.31 μM. DRI-C21041 inhibits the immune response induced by alloantigen.
    DRI-C21041
  • HY-160178
    Glucocorticoid receptor agonist-3 Ala-Ala-Mal
    		Inhibitor 99.72%
    Glucocorticoid receptor agonist-3 Ala-Ala-Mal (Compound Preparation 8) is an anti-human TNFα antibody-glucocorticoid receptor agonist (GC) conjugate. Glucocorticoid receptor agonist-3 Ala-Ala-Mal can be used in the study of autoimmune and inflammatory diseases.
    Glucocorticoid receptor agonist-3 Ala-Ala-Mal
  • HY-N3979
    Grossamide
    		Inhibitor 98.0%
    Grossamide is a natural product that can be isolated from fructus cannabis, the dried fruit of Cannabis sativa L.. Grossamide has anti-neuroinflammatory effects.
    Grossamide
  • HY-12085S
    Apremilast-d5
    		Inhibitor 99.26%
    Apremilast-d5 is a deuterium labeled Apremilast. Apremilast 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>5</sub>
  • HY-N0619A
    cis-Mulberroside A
    		Inhibitor
    cis-Mulberroside A (Mulberroside D) is the cis-isomer of Mulberroside A. Mulberroside A is one of the main bioactive constituent in mulberry (Morus alba L.). Mulberroside A decreases the expressions of TNF-α, IL-1β, and IL-6 and inhibits the activation of NALP3, caspase-1, and NF-κB and the phosphorylation of ERK, JNK, and p38, exhibiting anti-inflammatory and anti-apoptotic effects. Mulberroside A shows inhibitory activity against mushroom tyrosinase with an IC50 of 53.6 μM.
    cis-Mulberroside A
  • HY-129151
    Ganoderic acid C1
    		Inhibitor
    Ganoderic acid C1, a natural compound that could be isolated from G. lucidum, suppresses TNF-α production by murine macrophages (RAW 264.7 cells).
    Ganoderic acid C1
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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