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-102040
    Hispidol
    		Inhibitor 98.30%
    Hispidol ((Z)-Hispidol) is a potential therapeutic for inflammatory bowel disease; inhibits TNF-α induced adhesion of monocytes to colon epithelial cells with an IC50 of 0.50 μM.
    Hispidol
  • HY-107352
    Fosfenopril
    		Inhibitor 99.89%
    Fosfenopril (Fosinoprilat) is a potent angiotensin converting enzyme (ACE) inhibitor. Fosfenopril alleviates lipopolysaccharide (LPS)-induced inflammation by inhibiting TLR4/NF-κB signaling in monocytes.
    Fosfenopril
  • HY-123885
    NSC243928 mesylate
    		99.33%
    NSC243928 mesylate is a human lymphocyte antigen 6 (LY6) binder, which also acts as an inhibitor of cell growth and has anticancer activity.
    NSC243928 mesylate
  • HY-P990070
    Zigakibart
    		Inhibitor 99.85%
    Zigakibart (BION-1301) is an IgG4-kappa, anti-TNFSF13 (tumor necrosis factor (TNF) superfamily member 13, APRIL, CD256) humanized monoclonal antibody. Zigakibart shows anti-inflammatory activity.
    Zigakibart
  • HY-B0513
    Methylthiouracil
    		Inhibitor ≥98.0%
    Methylthiouracil is an antithyroid agent. Methylthiouracil suppresses the production TNF-α and IL-6, and the activation of NF-κB and ERK1/2.
    Methylthiouracil
  • HY-P2612A
    WP9QY TFA
    		Antagonist 99.83%
    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 TFA
  • HY-N6255
    Ilexgenin A
    		98.33%
    Ilexgenin A is a pentacyclic triterpenoid, which extracted from Ilex hainanensis Merr. Ilexgenin A can be used for the research of inflammation and cancer.
    Ilexgenin A
  • HY-100176
    PF-4878691
    		99.89%
    PF-4878691 (3M-852A) is an orally active TLR7 agonist. PF-4878691 has the innate immune response activity, antiviral efficacy against HCV, and can be used for the research of cancer.
    PF-4878691
  • HY-W026772
    Fluorene
    		Activator 99.35%
    Fluorene is an orally active polycyclic aromatic hydrocarbon (PAH) and a precursor to other fluorene-based compounds. Fluorene and its derivatives serve as dye precursors for fluorene synthesis. In A549 cells, Fluorene induces oxidative stress and inflammatory responses by increasing ROS and SOD generation, exacerbating lipid peroxidation, modulating antioxidant enzyme activity, and upregulating the expression of pro-inflammatory factors TNF-α and IL-6. In vivo, Fluorene exhibits anxiolytic activity. Fluorene holds potential for research in inflammation and neurological disorders.
    Fluorene
  • HY-P990083
    Tegoprubart
    		99.90%
    Tegoprubart is a monoclonal antibody directed against CD40 ligand (CD40L), a key mediator of costimulation. Inhibition of CD40L reduces cellular and antibody-mediated immunity and creates a more tolerant immune environment. Tegoprubart was demonstrated to have in vivo efficacy in transplantation animal models.
    Tegoprubart
  • HY-P99393
    Tavolixizumab
    		Inhibitor 99.76%
    Tavolixizumab (MEDI 0562; Tavolimab) is a human monoclonal antibody to TNFRSF4 (TNF receptor superfamily member 4) for use in cancer immunology research.
    Tavolixizumab
  • HY-115620
    AQX-016A
    		Inhibitor 98.00%
    AQX-016A is an orally active and potent SHIP1 agonist. AQX-016A can activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity. AQX-016A also can inhibit the PI3K pathway and TNFa production, can be useful for various inflammatory diseases research.
    AQX-016A
  • HY-P990134
    Anti-Mouse CD40L/CD154 Antibody (MR-1)
    		Inhibitor 99.62%
    Anti-Mouse CD40L/CD154 Antibody (MR-1) is a Armenian hamster-derived IgG type antibody inhibitor, targeting to mouse CD40L/CD154.
    Anti-Mouse CD40L/CD154 Antibody (MR-1)
  • HY-120299
    KC01
    		Inhibitor ≥99.0%
    KC01 is an effective inhibitor of ABHD16A, with IC50s of 90 nM for hABHD16A and 520 nM for mABHD16A. KC01 significantly reduces lyso-PSs, and decreases lyso-PS and LPS-induced cytokine production in mouse macrophages .
    KC01
  • HY-N2252
    Licarin A
    		Inhibitor 98.48%
    Licarin A ((+)-Licarin A), a neolignan, significantly and dose-dependently reduces TNF-α production (IC50=12.6 μM) in dinitrophenyl-human serum albumin (DNP-HSA)-stimulated RBL-2H3 cells. Anti-allergic effects. Licarin A reduces TNF-α and PGD2 production, and COX-2 expression.
    Licarin A
  • HY-N0358
    1,4-Dicaffeoylquinic acid
    		Inhibitor 98.44%
    1,4-Dicaffeoylquinic acid (1,4-DCQA) is a phenylpropanoid compound that can be isolated from Xanthii fructus and an inhibitor of xanthine oxidase (IC50: 7.36 μM). 1,4-Dicaffeoylquinic acid has anti-inflammatory activity and can inhibit the production of TNF-α induced by LPS (HY-D1056).
    1,4-Dicaffeoylquinic acid
  • HY-N7102
    Ceftiofur
    		Inhibitor 99.06%
    Ceftiofur is a cell wall synthesis inhibitor that targets bacterial penicillin-binding proteins (PBPs) and has anti-inflammatory effects in endotoxemia. Ceftiofur exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycan, leading to bacterial cell lysis. Ceftiofur also inhibits the activation of NF-κB and MAPKs, thereby reducing the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6.
    Ceftiofur
  • HY-125740
    Malvidin-3-glucoside chloride
    		Inhibitor 99.87%
    Malvidin-3-glucoside (Malvidin-3-O-glucoside; Oenin) chloride is an orally active inhibitor of the NF-κB pathway, which blocks inflammatory responses induced by TNF-α, reduces IκB-α degradation and p65 nuclear translocation, and upregulates endothelial nitric oxide synthase eNOS to increase NO production. Malvidin-3-glucoside chloride exerts anti-inflammatory and antioxidant effects by inhibiting pro-inflammatory molecules such as MCP-1, ICAM-1, and IL-6, and regulating intestinal microorganisms and metabolites, while protecting endothelial cells and improving intestinal microecological dysbiosis under inflammatory conditions. Malvidin-3-glucoside chloride can be used to study chronic inflammatory-related diseases such as atherosclerosis and inflammatory bowel disease, and has the potential to prevent vascular inflammation and improve intestinal health.
    Malvidin-3-glucoside chloride
  • HY-112642
    9-Methoxycanthin-6-one
    		Inhibitor 99.80%
    9-Methoxycanthin-6-one, a canthin-6-one alkaloid, is present in intact plant parts and in callus tissues of different explants. 9-Methoxycanthin-6-one shows anti-tumor activity, inhibits LPS-induced TNF-α and IL-1β.
    9-Methoxycanthin-6-one
  • HY-155751
    HMGB1-IN-1
    		Inhibitor 99.37%
    HMGB1-IN-1 (compound 6) displays strong NO inhibitory effect in RAW264.7 cells with IC50 value of 15.9 ± 0.6 μM. HMGB1-IN-1 inhibit the HMGB1/NF-κB/NLRP3 pathway. HMGB1-IN-1 shows good anti-inflammatory activity and good anti-sepsis effects in kidney injury.
    HMGB1-IN-1
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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