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-W1000105
    Geranial
    		Inhibitor 99.51%
    Geranial ((E)-3,7-Dimethylocta-2,6-dienal) is a derivative of geraniol with anti-inflammatory activity. Geranial can inhibit the secretion of TNF-α and IL-6 in macrophages. Furthermore, Geranial also inhibits the secretion of IL-1β mediated by the NLRP-3 inflammasome.
    Geranial
  • HY-P990133
    Anti-Monkey/Human CD40L/CD154 Antibody (5C8)
    		Inhibitor
    Anti-Monkey/Human CD40L/CD154 Antibody (5C8) is a mouse-derived IgG2a type antibody inhibitor, targeting to monkey/human CD40L/CD154. Anti-Monkey/Human CD40L/CD154 Antibody (5C8) blocks the interactionbetween CD154 and CD40. Anti-Monkey/Human CD40L/CD154 Antibody (5C8) can be used for the researches of inflammation and immunology, such as colitis and transplant.
    Anti-Monkey/Human CD40L/CD154 Antibody (5C8)
  • HY-P990715
    Ozekibart
    		99.63%
    Ozekibart is an anti-TNFRSF10B monoclonal antibody.
    Ozekibart
  • HY-P991049
    Atrosimab
    		Inhibitor 98.00%
    Atrosimab (ATM-001) is a Fv-Fc1κ fusion protein with strong binding to human TNFR1 with an EC50 value of 0.37 nM. Atrosimab potently inhibits TNF-induced activation of TNFR1. Atrosimab has the potential for the study of chronic inflammatory diseases.
    Atrosimab
  • HY-P990907
    Brivekimig
    		Inhibitor 98%
    HY-P990907 is an TNFSF4/TNFSF2/ALB-targeting VH-VH-VH-VH-VH type chimeric antibody.
    Brivekimig
  • HY-15643A
    LY 303511 hydrochloride
    		Activator 98.87%
    LY 303511 hydrochloride is a structural analogue of LY294002. LY303511 does not inhibit PI3K. LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells. LY303511 reversibly blocks K+ currents (IC50=64.6±9.1 μM) in MIN6 insulinoma cells.
    LY 303511 hydrochloride
  • 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-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-P1875
    TNF-α (46-65), human
    		98.68%
    TNF-α (46-65), human is a peptide of TNF-α.
    TNF-α (46-65), human
  • HY-N2263
    Skimmin
    		99.64%
    Skimmin (Umbelliferone glucoside) is a major pharmacologically active and orally active molecule present in Hydrangea paniculata, a medical herb used in traditional Chinese medicine as an anti-inflammatory agent. Skimmin has renal protective activity. Skimmin can improve creatinine clearance, and reduce plasma creatinine, and kidney injuries. Skimmin has good anti-amoebic activity against the HM1:IMMS strain of Entamoeba histolytica. Skimmin has anti-cancer and neuroprotective activities. Skimmin reduces cardiac fibrosis as well as decreasing TNF-α, IL-6, IL1β, and TGFβ1 in cardiac tissues. Skimmin can be studied in research for diabetes and diabetes-related diseases.
    Skimmin
  • 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-154822
    DRI-C25441
    		Inhibitor 99.53%
    DRI-C25441 is a potent blocker of CD40 and CD40L interaction, with an IC50 of 0.36 μM. DRI-C25441 can inhibit the immune response induced by alloantigen. can inhibit CD40L induced activation of NF-κB signaling pathway. DRI-C25441 commonly is used in research on immune conditions .
    DRI-C25441
  • 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-N7102
    Ceftiofur
    		Inhibitor 99.81%
    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-110036A
    GW405833 hydrochloride
    		Inhibitor 99.59%
    GW405833 (L768242) hydrochloride is a potent, selective cannabinoid receptor 2 (CB2) agonist. GW405833 has EC50 and Ki values ​​of 0.65 nM and 3.92 nM for CB2, and EC50 and Ki values ​​of 16.1 μM and 4772 nM for CB1. GW405833 hydrochloride also exhibits non-competitive CB1 antagonist, exerting its analgesic effect through a CB1 receptor (rather than CB2) dependent mechanism. GW405833 hydrochloride can significantly inhibit the production of cAMP stimulated by Forskolin (HY-15371). GW405833 hydrochloride inhibits glycolysis by down-regulating HIF-1α, thereby alleviating acute liver failure (ALF).
    GW405833 hydrochloride
  • HY-171034
    PQA-18
    		Inhibitor 99.62%
    PQA-18 is a unique PAK2 inhibitor (IC50: 10 nM). PQA-18 has immunosuppressing effects. PQA-18 suppresses IL2, IL4, IL6, and TNFα. PQA-18 inhibits the population of a subset of regulatory T cells and the immunoglobulin (Ig) production against T cell-dependent antigens as well as alleviates dermatitis in mice.
    PQA-18
  • HY-107390A
    AX-024 hydrochloride
    		Inhibitor 99.23%
    AX-024 hydrochloride is an orally available, first-in-class inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 ~1 nM. AX-024 hydrochloride modulates cell signaling by targeting SH3 domains. AX-024 hydrochloride has low-acute toxicity and high potency and selectivity, and strongly inhibit the production of IL-6, TNF-α, IFN-γ, IL-10 and IL-17A.
    AX-024 hydrochloride
  • HY-B0446
    Naphazoline hydrochloride
    		Inhibitor 99.38%
    Naphazoline (Naphthazoline) hydrochloride is a potent α-adrenergic receptor agonist. Naphazoline hydrochloride reduces vascular hyperpermeability and promotes vasoconstriction. Naphazoline hydrochloride reduces the levels of inflammatory factors (TNF-α, IL-1β and IL-6), cytokines (IFN-γ and IL-4), IgE, GMCSF, and NGF. Naphazoline hydrochloride can be used for non-bacterial conjunctivitis research.
    Naphazoline hydrochloride
  • HY-W115786
    Kaolin
    		Activator
    Kaolin is a family of kaolinitic clays, which is found in the earth's crust. Kaolin alleviates the toxicity of graphene oxide for mammalian cells. Kaolin can be utilized in industrial, cosmetic and medical fields, excipient.
    Kaolin
  • HY-N7513
    Homovanillyl alcohol
    		99.84%
    Homovanillyl alcohol is a biological metabolite of Hydroxytyrosol. Hydroxytyrosol is a phenolic compound that is present in virgin olive oil (VOO) and wine. Homovanillyl alcohol protects red blood cells (RBCs) from oxidative injury and has protective effect on cardiovascular disease.
    Homovanillyl alcohol
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. 
 

TNF Receptor Isoform Comparison

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