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-12220
    MM-102
    		Inhibitor 99.39%
    MM-102 (HMTase Inhibitor IX) is a cell-permeable and tightly binding inhibitor of MLL1-WDR5 interaction (IC50=2.4 nM). MM-102 can specifically inhibit the growth and induce apoptosis of leukemia cells containing MLL1 fusion protein, and reduce renal fibrosis and inflammation in mice with ischemia-reperfusion injury. In addition, MM-102 also acts as an H3K4 histone methyltransferase inhibitor to improve the development of porcine somatic cell nuclear transfer (SCNT) embryos.
    MM-102
  • HY-P99111
    Golimumab
    		Inhibitor 99.71%
    Golimumab (CNTO-148) is a potent human IgG1 TNFα antagonist monoclonal antibody. Golimumab has anti-inflammation activitity and inhibits IL-6 and IL-1β production. Golimumab acts via targeting and neutralizing TNF to prevent inflammation and destruction of cartilage and bone. Golimumab has the anticancer activity and induces cell apoptosis. Golimumab can be used for rheumatoid arthritis, Crohn's disease and cancer research.
    Golimumab
  • HY-147045
    UCB-5307
    		Inhibitor
    UCB-5307 is a potent TNF signaling inhibitor with a KD of 9 nM for human TNFα. UCB-5307 can penetrate the preformed hTNF/hTNFR1 complex.
    UCB-5307
  • HY-B0679
    Lubiprostone
    		Antagonist ≥98.0%
    Lubiprostone (SPI-0211; RU0211) increases intestinal fluid secretion through generation of CIC-2/CFTR and activation of cAMP signaling pathway. Lubiprostone inhibits myeloperoxidase (MPO) activity, downregulates Indomethacin (HY-14397)-induced iNOS and TNFα expression. Lubiprostone can be used for chronic constipation research.
    Lubiprostone
  • HY-150725
    ODN 1585
    		Inducer
    ODN 1585 is a potent inducer of IFN and TNFα production. ODN 1585 is a potent stimulator of NK (natural killer) function. ODN 1585 increases CD8+ T-cell function, including the CD8+ T cell-mediated production of IFN-γ. ODN 1585 induces regression of established melanomas in mice. ODN 1585 can confer complete protection against malaria in mice. ODN 1585 can be used for acute myelogenous leukemia (AML) and malaria research. ODN 1585 can be used as a vaccine adjuvant.
    ODN 1585
  • HY-156454
    UCB-6876
    		Inhibitor 99.96%
    UCB-6876 is a TNFα inhibitor and binds to asymmetrical crystal form of the TNF trimer (KD=22 μM).
    UCB-6876
  • HY-101849
    Fasentin
    		Agonist ≥98.0%
    Fasentin, a potent glucose uptake inhibitor, inhibits GLUT-1/GLUT-4 transporters. Fasentin preferentially inhibits GLUT4 (IC50=68 μM) over GLUT1. Fasentin is a death receptor stimuli (FAS) sensitizer and sensitizes cells to FAS-induced cell death. Fasentin is also a tumor necrosis factor (TNF) apoptosis-inducing ligand sensitizer. Fasentin blocks glucose uptake in cancer cell lines and has anti-angiogenic activity.
    Fasentin
  • HY-N1949
    Homoplantaginin
    		Inhibitor 99.90%
    Homoplantaginin is a flavonoid from a traditional Chinese medicine Salvia plebeia with antiinflammatory and antioxidant properties. Homoplantaginin could inhibit TNF-α and IL-6 mRNA expression, IKKβ and NF-κB phosphorylation.
    Homoplantaginin
  • HY-15509A
    Semapimod tetrahydrochloride
    		Inhibitor 98.43%
    Semapimod tetrahydrochloride (CNI-1493), an inhibitor of proinflammatory cytokine production, can inhibit TNF-α, IL-1β, and IL-6. Semapimod tetrahydrochloride inhibits TLR4 signaling (IC50≈0.3 μM). Semapimod tetrahydrochloride inhibits p38 MAPK and nitric oxide production in macrophages. Semapimod tetrahydrochloride has potential in a variety of inflammatory and autoimmune disorders.
    Semapimod tetrahydrochloride
  • HY-133807
    Benpyrine
    		Inhibitor 99.74%
    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.
    Benpyrine
  • HY-145588
    Povorcitinib
    		Antagonist 99.00%
    Povorcitinib (INCB54707) is a potent and selective JAK1 inhibitor that effectively reduces abscesses and inflammatory nodules. Povorcitinib is used to study cutaneous lupus erythematosus (CLE) and lichen planus (LP).
    Povorcitinib
  • HY-100755
    KR-33493
    		Inhibitor 99.94%
    KR-33493 is a potent inhibitor of Fas-mediated cell death (FAF1).
    KR-33493
  • HY-P99796
    Ozoralizumab
    		Inhibitor 99.80%
    Ozoralizumab (ATN-103) is an anti-TNFα humanized antibody. Ozoralizumab is a humanized trivalent nanobody compound that consists of two anti-human TNFα nanobodies and an anti-human serum albumin (HSA) nanobody. Ozoralizumab can be used in research of arthritis.
    Ozoralizumab
  • HY-B0766
    Bicyclol
    		Inhibitor 99.91%
    Bicyclol (SY801) is an orally active derivative of the traditional Chinese medicine Schisandra chinensis, which has antiviral, anti-inflammatory, immunomodulatory, antioxidant, anti-steatosis, anti-fibrotic and anti-tumor activities. Bicyclol regulates the expression of heat shock proteins and plays an anti-apoptosis role in hepatocytes. Bicyclol reduces the activation of NF-κB and the levels of inflammatory factors in hepatocytes infected with hepatitis C virus (HCV) by inhibiting the activation of the ROS-MAPK-NF-κB pathway, and prevents ferroptosis in acute liver injury. Bicyclol can change the expression of Mdr-1, GSH/GST and Bcl-2, increase the intracellular concentration of anticancer drugs, and sensitize drug-resistant cells to anticancer drugs. Bicyclol inhibits the proliferation of human malignant hepatoma cells by regulating the PI3K/AKT pathway and the Ras/Raf/MEK/ERK pathway. Bicyclol can be used in the study of chronic hepatitis, acute liver injury, nonalcoholic fatty liver disease, liver fibrosis and hepatocellular carcinoma.
    Bicyclol
  • HY-N2195
    Nootkatone
    		Inhibitor 99.84%
    Nootkatone, a neuroprotective agent from Vitis vinifera, has antioxidant and anti-inflammatory effects. Nootkatone improves cognitive impairment in lipopolysaccharide-induced mouse model of Alzheimer's disease.
    Nootkatone
  • HY-N2464
    Maltotetraose
    		99.88%
    Maltotetraose can serve as a substrate for enzyme-linked assays to measure amylase activity in biological fluids. Maltotetraose has oral active, and reduces TNF-α-induced inflammatory responses by inhibiting NF-κB activity and decreasing ICAM-1 expression. Maltotetraose also inhibits PDGF-induced vascular smooth muscle cell migration and neovascularization. Additionally, Maltotetraose derivatives can function as probes for detecting bacterial infections by targeting the maltodextrin transporter. With good long-term safety, Maltotetraose holds promise for research in atherosclerosis-related diseases.
    Maltotetraose
  • HY-N2963
    Broussonin E
    		Inhibitor 98.18%
    Broussonin E is a phenolic compound and shows anti-inflammatory activity. Broussonin E can suppress inflammation by modulating macrophages activation statevia inhibiting the ERK and p38 MAPK and enhancing JAK2-STAT3 signaling pathway. Broussonin E can be used for the research of inflammation-related diseases such as atherosclerosis.
    Broussonin E
  • HY-N6739
    Beauvericin
    		99.97%
    Beauvericin is a cyclohexapeptide Fusarium toxin with insecticidal, antibacterial, anticancer, antiviral and cytotoxic activities. Beauvericin causes cellular genotoxicity by producing DNA breaks, chromosomal aberrations and micronuclei, and inhibits the PI3K/AKT pathway to induce apoptosis, thereby inhibiting the growth of HCC. In addition, Beauvericin affects immune function by inhibiting lymphocyte proliferation and interfering with the differentiation process of human monocytes into macrophages.
    Beauvericin
  • HY-N0042
    Ginsenoside Rc
    		Inhibitor ≥98.0%
    Ginsenoside Rc, one of major Ginsenosides from Panax ginseng, enhances GABA receptorA (GABAA)-mediated ion channel currents (IGABA). Ginsenoside Rc inhibits the expression of TNF-α and IL-1β.
    Ginsenoside Rc
  • HY-P1068
    Lysozyme
    		Inhibitor
    Lysozyme (Muramidase) is a conserved antimicrobial protein. Lysozyme exerts its bactericidal effect by hydrolyzing bacterial cell wall peptidoglycan (PG). Lysozyme plays an important role in limiting bacterial growth on mucosal surfaces and other sites, not only controlling potential pathogens but also limiting overgrowth of microbiota to prevent dysbiosis. Extracellular lysozyme can also degrade polymeric PG into soluble fragments, activate NOD receptors in mucosal epithelial cells, and lead to the secretion of chemokines and activating factors by neutrophils and macrophages.
    Lysozyme
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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