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-N3541
    Cardenolide B-1
    		Inhibitor
    Cardenolide B-1 is a Steroids product that can be isolated from the herbs of Nerium oleander.
    Cardenolide B-1
  • HY-107632G
    GYY4137 (GMP)
    		Inhibitor
    GYY4137 (GMP) is the GMP-grade version of GYY4137 (HY-107632). Small molecules of GMP grade can be used as adjuvant reagents in cell therapy. GYY4137 (GMP) is a sustained-release H2S donor possessing vasodilatory, antihypertensive, and anti-inflammatory activities. GYY4137 (GMP) can inhibit cell growth, induce apoptosis, and cause cell cycle arrest by blocking the STAT3 pathway, demonstrating potent anticancer activity.
    GYY4137 (GMP)
  • HY-20070
    BMS-566394
    		Inhibitor
    BMS-566394 is a potent inhibitor of tumor necrosis factor-α (TNF-α) converting enzyme (TACE) that helps reduce the production of TNF-α, thereby alleviating inflammation and immune-mediated diseases and can be used in the study of inflammatory and autoimmune diseases.
    BMS-566394
  • HY-N1125
    Triptobenzene H
    		Inhibitor
    Triptobenzene H (Hypoglic acid) significantly increases TNF-α and IL-1β mRNA levels in macrophages, causing indirect liver damage.
    Triptobenzene H
  • HY-N11994
    Aloeresin G
    		Inhibitor
    Aloeresin G is a chromone glycoside that can be isolated from Aloe. Aloeresin G has a weak inhibitory effect on TNFα-induced NF-κB transcriptional activity, with an IC 50 value of 40.02 μM.
    Aloeresin G
  • HY-N7102R
    Ceftiofur (Standard)
    		Inhibitor
    Ceftiofur (Standard) is the analytical standard of Ceftiofur (HY-N7102). This product is intended for research and analytical applications. 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 (Standard)
  • HY-B0898S
    Ceftiofur-d3 sodium
    		Inhibitor
    Ceftiofur-d3 sodium is deuterium labeled Ceftiofur sodium (HY-B0898). Ceftiofur sodium is a cell wall synthesis inhibitor that targets bacterial penicillin-binding proteins (PBPs) and has anti-inflammatory effects in endotoxemia. Ceftiofur sodium exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycan, leading to bacterial cell lysis. Ceftiofur sodium 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-d<sub>3</sub> sodium
  • HY-N0619R
    Mulberroside A (Standard)
    		Inhibitor
    Mulberroside A (Standard) is the analytical standard of Mulberroside A. This product is intended for research and analytical applications. Mulberroside A is one of the main bioactive constituent in mulberry (Morus alba L.). Mulberroside A decreases the expressions of TNF-α, IL-1β, and IL-6 and inhibits the activation of NALP3, caspase-1, and NF-κB and the phosphorylation of ERK, JNK, and p38, exhibiting anti-inflammatory antiapoptotic effects. Mulberroside A shows inhibitory activity against mushroom tyrosinase with an IC50 of 53.6 μM.
    Mulberroside A (Standard)
  • HY-116426
    IDT
    		Modulator
    IDT is a safe and effective TNFα and innate immune system modulator. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation and increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT can be used in Alzheimer's disease research.
    IDT
  • HY-B0809S1
    Theophylline-d3
    		Inhibitor
    Theophylline-d3 is deuterated labeled Theophylline (HY-B0809). 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-d<sub>3</sub>
  • HY-B0679R
    Lubiprostone (Standard)
    		Antagonist
    Lubiprostone (Standard) is the analytical standard of Lubiprostone. This product is intended for research and analytical applications. Lubiprostone (SPI-0211) 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 (Standard)
  • HY-168782
    Resolvin D2 n-3 DPA
    		Inhibitor
    Resolvin D2 n-3 DPA is a specialized proresolving mediator (SPM). Resolvin D2 n-3 DPA (1 nM) can reduce the chemotaxis and adhesion of human neutrophils induced by TNF-α. Resolvin D2 n-3 DPA (100 ng/mouse; intravenous injection) can reduce neutrophil infiltration in the peritoneum and the levels of IL-6 and the chemokine (C-C motif) ligand 2 (CCL2) in a mouse model of inflammation induced by zinc oxide.
    Resolvin D2 n-3 DPA
  • HY-163915
    8-(4-(Trifluoromethyl)anilino)quercetin
    		Inhibitor
    8-(4-(Trifluoromethyl)anilino)quercetin is a potent ErmA inhibitor. 8-(4-(Trifluoromethyl)anilino)quercetin has antioxidant and anti-inflammatory activity.
    8-(4-(Trifluoromethyl)anilino)quercetin
  • HY-N0635R
    Prim-O-glucosylcimifugin (Standard)
    Prim-O-glucosylcimifugin (Standard) is the analytical standard of Prim-O-glucosylcimifugin. This product is intended for research and analytical applications. Prim-O-glucosylcimifugin exerts anti-inflammatory effects through the inhibition of iNOS and COX-2 expression by through regulating JAK2/STAT3 signaling.
    Prim-O-glucosylcimifugin (Standard)
  • HY-156431
    Anti-inflammatory agent 61
    		Inhibitor
    Anti-inflammatory agent 61 (Compound 5b) is a potent anti-inflammatory agent. Anti-inflammatory agent 61 reduces TNF-α expression in LPS-induced inflammation in RAW 264.7 cells. Anti-inflammatory agent 61 alleviates APAP-induced inflammation in HepG2 cells.
    Anti-inflammatory agent 61
  • HY-173595
    ODE-(S)-HPMPA formate
    		Activator
    ODE-(S)-HPMPA formate is an antiviral compound with strong inhibitory activity against poxviruses and adenoviruses. ODE-(S)-HPMPA formate activates TNF-α secretion.
    ODE-(S)-HPMPA formate
  • HY-134070
    2-O-Methyl PAF C-16
    		Activator
    2-O-Methyl PAF C-16 (ET-18-O-OCH3), a structural analog of the mediator of inflammation platelet-activating factor (PAF), is a cytotoxic ether lipid. 2-O-Methyl PAF C-16 stimulates TNF-α release in murine macrophages.
    2-O-Methyl PAF C-16
  • HY-N15496
    Fusaproliferin
    		Inhibitor
    Fusaproliferin is a sesterterpene mycotoxin isolated from Fusarium solani. Fusaproliferin reverse Lipopolysaccharides (HY-D1056) stimulation and the NF-κB and MAPKs signaling pathways contribute to the anti-inflammatory process. Fusaproliferin exhibits affinity for the TLR4 protein with KD values of 28.6 μM. Fusaproliferin shows cytotoxicity against pancreatic cancer cell with rapid and sub-micromolar IC50.
    Fusaproliferin
  • HY-N12116
    Maceneolignan A
    		Inhibitor
    Maceneolignan A is a natural product that can be isolated from mace, the aril of Myristica fragrans (Myristicaceae). Maceneolignan A inhibits the release of β-hexosaminidase in RBL-2H3 cells, with an IC50 of 48.4 μM. Maceneolignan A inhibits the release of TNF-α in antigen stimulated RBL-2H3 cells, with an IC50 of 63.7 μM.
    Maceneolignan A
  • HY-15643
    LY 303511
    		Activator
    LY303511 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
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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