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-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-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-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-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
  • HY-139066
    Punicic acid
    		Inhibitor 98.5%
    Punicic acid is a bioactive compound of pomegranate seed oil. Punicic acid is an isomer of conjugated α-linolenic acid and ω-5 polyunsaturated fatty acids. Punicic acid has anti-inflammatory and antioxidant activities and can inhibit the expression of inflammatory mediators such as tumor necrosis factor α (TNF-α). Punicic acid can also reduce the formation of β-amyloid deposits and hyperphosphorylation of tau by increasing the expression of GLUT4 protein and inhibiting the overactivation of calpain, and is used to prevent and treat neurodegenerative diseases. In addition, punicic acid also has breast cancer inhibitor properties that depend on lipid peroxidation and PKC pathways.
    Punicic acid
  • HY-B2162D
    Chondroitin sulfate (from chicken)
    		Inhibitor 99.61%
    Chondroitin sulfate (from chicken) (Chondroitin polysulfate (from chicken)) is an orally active, sulfated linear polysaccharide extracted from chickens, which belongs to glycosaminoglycans. Chondroitin sulfate (from chicken) reduces the phosphorylation levels of ERK1/2 and p38MAPK, inhibits the expression of inflammatory cytokines and MMP, and downregulates the levels of IL-1β, IL-6, TNF-α and PGE2. Chondroitin sulfate (from chicken) improves motor function, protects cartilage tissue, reverses chondrocyte aggregation, and regulates the structure of intestinal flora. Chondroitin sulfate (from chicken) can be used in research related to osteoarthritis.
    Chondroitin sulfate (from chicken)
  • HY-N0594
    Deacetylasperulosidic Acid
    		Inhibitor 99.44%
    Deacetylasperulosidic Acid is an orally active antioxidant. Deacetylasperulosidic Acid exerts a definite in vivo antioxidant effect and alleviates oxidative stress injury by enhancing SOD activity. In atopic dermatitis models, Deacetylasperulosidic Acid corrects Th2-skewed immune imbalance and reduces allergy-related factors; in immunosuppression models, it activates cellular immunity, enhances NK cell activity and IL-2 production. Deacetylasperulosidic Acid can be used in the research of atopic dermatitis.
    Deacetylasperulosidic Acid
  • HY-N2086
    Ethyl palmitate
    		Inhibitor 99.09%
    Ethyl palmitate (Ethyl hexadecanoate) is a CHIKV virus inhibitor with an EC50 value of 0.0068 μM. Ethyl palmitate can reduce levels of TNF-α, IL-6, and NF-κB in endotoxemic rats, showing anti-inflammatory activity.
    Ethyl palmitate
  • HY-P10086
    TREM-1 inhibitory peptide GF9
    		Inhibitor 99.41%
    TREM-1 inhibitory peptide GF9 (Human TREM-1 (213-221)) is a TREM-1 inhibitor. TREM-1 inhibitory peptide GF9 blocks the TREM-1 signaling pathway via a ligand-independent mechanism, spontaneously inserts into the cell membrane to dissociate TREM-1 from DAP-12, and functions through the Signaling Chain Homooligomerization (SCHOOL) model. TREM-1 inhibitory peptide GF9 reduces the levels of TNFα, IL-1β, IL-6, and M-CSF. TREM-1 inhibitory peptide GF9 inhibits tumor growth, prolongs the survival of mice with pancreatic cancer models, ameliorates collagen-induced arthritis, and exerts protective effects on bone and cartilage simultaneously. TREM-1 inhibitory peptide GF9 can be used in research related to arthritis, pancreatic cancer, retinopathy, alcoholic liver disease, and liver cancer.
    TREM-1 inhibitory peptide GF9
  • HY-139481
    TL-895
    		Inhibitor 99.86%
    TL-895 is a potent, orally active, ATP-competitive, and highly selective irreversible BTK inhibitor. TL-895 is active against recombinant BTK (average IC50: 1.5 nM) and inhibits only three additional kinases BLK, BMX (IC50 = 1.6 nM) and TXK with IC50 within tenfold of BTK activity. TL-895 inhibits BTK auto-phosphorylation at the Y223 phosphorylation site (IC50: 1-10 nM). The TL-895 effectively inhibits the production of inflammatory factors such as IL-8, IL-1β, MCP-1 and TNF-α by monocytes or macrophages, and reduces the chemotactic migration of MF cells towards SDF-1. TL-895 is used be for studies of chronic lymphocytic leukemia (CLL), myelofibrosis (MF), and B-cell malignancies.
    TL-895
  • HY-P99149
    Anti-Mouse TNFR2 Antibody (TR75-54.7)
    		Inhibitor 98.864%
    Anti-Mouse TNFR2 Antibody (TR75-54.7) is an anti-mouse TNFR2 IgG monoclonal antibody. Anti-Mouse TNFR2 Antibody (TR75-54.7) can reduce white blood cell count (WBC) and decrease the expression of some pro-inflammatory cytokines such as CCL2 and CXCL5. Anti-Mouse TNFR2 Antibody (TR75-54.7) can be used for researches on inflammation conditions and cancer such as breast cancer.
    Anti-Mouse TNFR2 Antibody (TR75-54.7)
  • HY-P990742
    Givastomig
    		Inhibitor 98.556%
    Givastomig (ABL111, TJ033721) is a bispecific antibody (BsAb) inhibitor. Givastomig can specifically binds to Claudin18.2 (CLDN 18.2) on the surface of cancer cells and 4-1BB (CD137, TNFRSF9) on the surface of activated T cells and natural killer (NK) cells. Givastomig is engineered to contain a single Fc-domain mutation (asparagine to alanine) to eliminate Fc-effector function. Givastomig-bound cell lines expressing a range of CLDN18.2 levels with high affinity and induced 4-1BB activation only in the context of CLDN18.2 binding. Givastomig can be used for the study of colon carcinoma.
    Givastomig
  • HY-N2255
    Crebanine
    		Inhibitor 99.83%
    Crebanine is an isoquinoline-like alkaloid that can be derived from Stephania. Crebanine is an antagonist of the α7-nAChR with an IC50 of 19.1 μM. Crebanine suppresses the proliferation, migration, and invasion of cancer cells, triggers reactive oxygen species (ROS) burst, and promotes apoptosis. Crebanine inhibits the AKT/FoxO3a, NF-κB and MAPK signaling pathways. Crebanine attenuates NOX2 hyperactivation, exhibits antioxidant properties by reducing reactive oxygen species and peroxidation in microglia cells. Crebanine inhibits voltage-dependent Na+ current in guinea-pig ventricular myocytes. Crebanine has high inhibitory activity against gram-positive animal pathogenic bacteria. Crebanine ameliorates ischemia-reperfusion brain damage in middle cerebral artery occlusion and reperfusion (MCAO/R) rats. Crebanine significantly improves Scopolamine (HY-N0296)-induced cognitive deficits in ICR mice. Crebanine can be used for the study of hepatocellular carcinoma (HCC), cerebral ischemia and Alzheimer's disease.
    Crebanine
  • HY-20070
    BMS-566394
    		Inhibitor 99.95%
    BMS-566394 is a selective, orally active TACE (ADAM17) inhibitor. BMS-566394 inhibits LPS-induced TNF-α production in whole blood. BMS-566394 selectively inhibits TACE activity.
    BMS-566394
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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