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-135674
    SR-318
    		Inhibitor 98.17%
    SR-318, a chemical probe, is a potent and highly selective p38 MAPK inhibitor with IC50s of 5 nM, 32 nM and 6.11 μM for p38α, p38β and p38α/β, respectively. SR-318 potently inhibits the TNF-α release in whole blood with an IC50 of 283 nM. SR-318 has anti-cancer and anti-inflammatory activity.
    SR-318
  • HY-P99257
    Bleselumab
    		Inhibitor 98.97%
    Bleselumab (ASKP 1240) is a human anti-CD40 monoclonal antibody (mAb). Bleselumab binds to human CD40 with high affinity (Kd: 0.24 nM). Bleselumab inhibits immune responses by blocking the interaction of CD40 with its ligand CD40L. Bleselumab prevents organ transplant rejection.
    Bleselumab
  • HY-B0809R
    Theophylline (Standard)
    		Inhibitor
    Theophylline (Standard) is the analytical standard of Theophylline. This product is intended for research and analytical applications. Theophylline (1,3-Dimethylxanthine) is a potent phosphodiesterase (PDE) inhibitor, adenosine receptor antagonist, and histone deacetylase (HDAC) activator. Theophylline (1,3-Dimethylxanthine) inhibits PDE3 activity to relax airway smooth muscle. Theophylline (1,3-Dimethylxanthine) has anti-inflammatory activity by increase IL-10 and inhibit NF-κB into the nucleus. Theophylline (1,3-Dimethylxanthine) induces apoptosis. Theophylline (1,3-Dimethylxanthine) can be used for asthma and chronic obstructive pulmonary disease (COPD) research.
    Theophylline (Standard)
  • HY-N0631
    Cornuside
    		Inhibitor 99.99%
    Cornuside is an iridoid glycoside with anti-allergic, anti-inflammatory, and neuroprotective activities. Cornuside exerts anti-allergic activity by downregulating the p38 MAPK, JNK, and NF-κB signaling pathways, and inhibits IgE-mediated histamine release from mast cells. Cornuside improves cognitive impairment in mice by inhibiting BACE1 activity (IC50 = 55.84 μg/mL) and enhancing ChAT activity. Cornuside inhibits LPS (HY-D1056)-induced inflammatory mediators, including iNOS, COX-2, PGE2, TNF-α, IL-6, and IL-1β, by suppressing NF-κB activation.
    Cornuside
  • 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-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-169118
    EGR-1-IN-2
    		Inhibitor 99.61%
    EGR-1-IN-2 (compound 2) is an EGR-1 inhibitor with anti-inflammatory activity. EGR-1-IN-2 inhibits the formation of EGR-1-DNA complexes induced by TNF-α in HaCaT cells.
    EGR-1-IN-2
  • 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-P99812
    Ragifilimab
    		Agonist 99.32%
    Ragifilimab (INCAGN-1876) is an agonist monoclonal antibody targeting the glucocorticoid-induced TNFR-related protein (GITR). Ragifilimab binds to and activates GITR on T cells, which stimulates the immune system to enhance its anti-tumor activity. Ragifilimab can be used for advanced or metastatic solid tumors research.
    Ragifilimab
  • HY-113440
    5-Methoxytryptophol
    		Inhibitor 99.95%
    5-Methoxytryptophol is a 5-methoxyindole alcohol structurally homologous to Melatonin (HY-B0075). It is secreted by the mammalian pineal gland and exhibits an inverse circadian rhythm. 5-Methoxytryptophol regulates bone metabolism by activating the ERK1/2 pathway. It reduces the levels of pro-inflammatory cytokines TNF-α and IL-1β, as well as proteolytic enzymes MMP-1 and MMP-2, in serum and dental pulp tissues, thereby ameliorating acute pulpitis. 5-Methoxytryptophol induces rapid sleep in mice, while high doses cause respiratory depression and death. 5-Methoxytryptophol. 5-Methoxytryptophol can be used in studies related to acute pulpitis, hypnosis, and bone metabolism.
    5-Methoxytryptophol
  • HY-115620
    AQX-016A
    		Inhibitor 99.51%
    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-N5084
    Pinocembrin 7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-D-glucoside
    		98.92%
    Pinocembrin 7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-D-glucoside is a TRPV1 antagonist and HDAC7 inhibitor. Pinocembrin 7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-D-glucoside blocks TRPV1-mediated calcium influx, suppresses phosphorylation of p65, IκBα, p38, JNK, and ERK1/2, inhibiting NF-κB and MAPK signaling cascades. Pinocembrin 7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-D-glucoside reduces production and gene expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Pinocembrin 7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-D-glucoside exhibits potent analgesic activity, elevates thermal pain threshold and mechanical pain threshold in murine models. Pinocembrin 7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-D-glucoside restores CD8+ T cell infiltration into bladder cancer tumors and improves bladder cancer immunotherapy efficacy. Pinocembrin 7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-D-glucoside can be used for the researches of painand bladder cancer.
    Pinocembrin 7-O-[3''-O-galloyl-4'',6''-hexahydroxydiphenoyl]-β-D-glucoside
  • HY-N1921
    Edpetiline
    		Inhibitor 99.81%
    Edpetiline is an anti-inflammatory agent. Edpetiline inhibits the phosphorylation of IκB, nuclear transcription/translocation of NF-κB p65, as well as the phosphorylation of p38 MAPK and ERK MAPK. Edpetiline reduces intracellular ROS levels, inhibits the expression of TNF-α, IL-6, iNOS, COX-2, and promotes the expression of IL-4. Edpetiline is applicable to the research of diseases associated with inflammation and oxidative stress.
    Edpetiline
  • HY-N4285
    Negletein
    		Inhibitor 99.55%
    Negletein (5,6-Dihydroxy-7-methoxyflavone) is a flavone found in Scutellaria. Negletein shows anti-inflammatory activity via inhibiting TNF-α and IL-1β with IC50 values of 16.4 and 6.4 μM, respectively. Negletein can activate Nrf2 and inhibit ROS production. Negletein can enhance the neuroprotective effect of nerve growth factor. Negletein can inhibit amyloid beta-peptide release and accumulation. Negletein can inhibit pathogens biofilms formation. Negletein can be used for the researches of cancer, infection, inflammation and neurological disease, such as colon cancer and Alzheimer's disease.
    Negletein
  • 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-N0695
    Schisantherin B
    		Inhibitor 99.75%
    Schisantherin B (Gomisin-B) is a lignan compound and one of the active components of Schisandra chinensis. Schisantherin B activates the PI3K/AKT signaling pathway, restores the activity of GSK3β, and reduces the hyperphosphorylation of tau protein in hippocampal and cerebral cortical tissues. Schisantherin B upregulates the level of GLT-1, decreases the expression of pro-inflammatory cytokines TNF-α/IL-1β/IL-6, upregulates the expression of IL-10, and inhibits cell apoptosis. Schisantherin B is applicable to the research of spinal cord injury, Alzheimer's disease and depression.
    Schisantherin B
  • HY-B1197
    Amcinonide
    		Inhibitor 99.11%
    Amcinonide is an inhibitor of NO release (IC50 = 3.38 nM). Amcinonide inhibits NNC-induced expression of the proinflammatory genes iNOS, TNF-α, and IL-1β in glial cells. Amcinonide reduces the numbers of T6+/Ia+ cells with a concomitant increase in T6+/Ia- cells. Amcinonide induces a selective reduction in expression of Ia antigens. Amcinonide can also be studied in research for eczematous dermatitis.
    Amcinonide
  • HY-N6983
    Licoricesaponin G2
    		Inhibitor 99.87%
    Licoricesaponin G2 is an orally active component found in Licorice. Licoricesaponin G2 significantly ameliorates Bleomycin (HY-108345)-induced pulmonary fibrosis by inhibiting the TNF-α signaling pathway, reducing epithelial-mesenchymal transition, and decreasing extracellular matrix deposition. Licoricesaponin G2 inhibits cancer cells proliferation, migration, inhibits PI3K/AKT/mTOR signaling pathway and increases ROS production. Licoricesaponin G2 can be used for the research of lung cancer and pulmonary fibrosis.
    Licoricesaponin G2
  • HY-N0026
    2'-Acetylacteoside
    		Inhibitor 99.73%
    2'-Acetylacteoside (2'-AA) is a natural compound with oral activity and blood-brain barrier permeability. 2'-Acetylacteosideexhibits MAO‑B inhibitory activity (IC50 = 17.71 μM, Ki = 13.81 μM). 2'-Acetylacteoside downregulates the expression of RANK, TRAF6, NF‑κB, NFATc1 and IKKβ, disrupts the RANKL/RANK interaction, blocks downstream signaling pathways, and increases the level of phosphorylated Akt. 2'-Acetylacteoside possesses potent anti-osteoclastogenic, anti-bone resorptive, pro-neurogenic, neuroprotective and antioxidant activities. 2'-Acetylacteoside can be used in the research of osteoporosis, ischemic stroke and Parkinson's disease.
    2'-Acetylacteoside
  • HY-19717
    DCVC
    		Inhibitor 99.78%
    DCVC (S-[(1E)-1,2-Dichloroethenyl]-L-cysteine) is a bioactive metabolite of trichloroethylene (TCE). DCVC inhibits pathogen-stimulated pro-inflammatory cytokines IL-1β, IL-8, and TNF-α release from tissue cultures.
    DCVC
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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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