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-B0809A
    Theophylline monohydrate
    		Inhibitor 99.93%
    Theophylline (1,3-Dimethylxanthine) monohydrate is a potent phosphodiesterase (PDE) inhibitor, adenosine receptor antagonist, and histone deacetylase (HDAC) activator. Theophylline (1,3-Dimethylxanthine) monohydrate inhibits PDE3 activity to relax airway smooth muscle. Theophylline (1,3-Dimethylxanthine) monohydrate has anti-inflammatory activity by increase IL-10 and inhibit NF-κB into the nucleus. Theophylline (1,3-Dimethylxanthine) monohydrate induces apoptosis. Theophylline (1,3-Dimethylxanthine) monohydrate can be used for asthma and chronic obstructive pulmonary disease (COPD) research.
    Theophylline monohydrate
  • HY-123885
    NSC243928 mesylate
    		99.33%
    NSC243928 mesylate is a human lymphocyte antigen 6 (LY6) binder, which also acts as an inhibitor of cell growth and has anticancer activity.
    NSC243928 mesylate
  • HY-120299
    KC01
    		Inhibitor 99.0%
    KC01 is an effective inhibitor of ABHD16A, with IC50s of 90 nM for hABHD16A and 520 nM for mABHD16A. KC01 significantly reduces lyso-PSs, and decreases lyso-PS and LPS-induced cytokine production in mouse macrophages .
    KC01
  • 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-N6017
    Bakkenolide A
    		Inhibitor 99.99%
    Bakkenolide A is an anticancer agent. Bakkenolide A reduces the viability of leukemia cells, inhibits cell colony formation and invasion, and downregulates the expression of HDAC3 in cells. Bakkenolide A downregulates the expression of pro-inflammatory cytokines including TNF-α, interleukins such as IL-1β, TGF-β1 and IFN-γ, as well as the expression of PI3K, PDK and PKC in leukemia cells. Bakkenolide A downregulates activated Akt, GSK and Bad, while upregulates Cyto-c, cleaved Caspase3 and cleaved Caspase7, induces apoptosis (apoptosis) in leukemia cells and thereby inhibits inflammatory responses in leukemia cells. Bakkenolide A significantly slows the growth of subcutaneous leukemia tumors in nude mice. Bakkenolide A is applicable to leukemia-related research.
    Bakkenolide A
  • HY-N7926
    Pentadecane
    		Inhibitor 98.88%
    Pentadecane is an orally active natural plant volatile alkane with anti-inflammatory, analgesic, antipyretic and anti-leishmanial activities. Pentadecane presents IC50 values of 65.3 μM, 60.5 μM and 194.8 μM against Leishmania infantum promastigotes, amastigotes and intracellular amastigotes, respectively. Pentadecane downregulates the mRNA expression of TNF-α and IL-12 and inhibits the release of inflammatory mediators. Pentadecane arrests the cell cycle of Leishmania infantum and induces apoptosis. Pentadecane can be applied to the research of inflammation and leishmaniasis.
    Pentadecane
  • HY-N8277
    Kdo2-Lipid A ammonium
    		Inducer 99.00%
    Kdo2-Lipid A ammonium is a chemically defined lipopolysaccharide (LPS) with endotoxin activity equal to LPS. Kdo2-Lipid A ammonium is highly selective for TLR4. Kdo2-Lipid A ammonium stimulates the release of both TNF and PGE2.
    Kdo2-Lipid A ammonium
  • HY-112642
    9-Methoxycanthin-6-one
    		Inhibitor 99.80%
    9-Methoxycanthin-6-one, a canthin-6-one alkaloid, is present in intact plant parts and in callus tissues of different explants. 9-Methoxycanthin-6-one shows anti-tumor activity, inhibits LPS-induced TNF-α and IL-1β.
    9-Methoxycanthin-6-one
  • HY-118922
    IW927
    		Inhibitor 99.23%
    IW927 is a photochemically enhanced TNF-α-TNFR1 interaction inhibitor that blocks the binding of TNF-α to TNFRc1 with an IC50 value of 50 nM. IW927 binds reversibly to the TNFRc1 with weak affinity (Kd = 40-100 μM), covalently modifies the receptor via a photochemical reaction, and does not bind the related cytokine receptors TNFRc2 or CD40. IW927 disrupts TNFα-induced IκB phosphorylation with an IC50 value of 600 nM. IW927 can be used to develop light-independent inhibitors.
    IW927
  • HY-P990111
    BMS-986325 (anti-CD40)
    		Inhibitor 99.84%
    BMS-986325 (anti-CD40) is a CD40 inhibitor, and can be used for primary Sj gren's syndrome research.
    BMS-986325 (anti-CD40)
  • HY-145726A
    ISIS 104838 sodium
    		Inhibitor
    ISIS 104838 sodium is an antisense oligonucleotide targeting TNF-α. ISIS 104838 sodium specifically binds to human TNF-α mRNA via Watson-Crick base pairing to form a DNA:RNA hybrid duplex, thereby recruiting the ubiquitously expressed intracellular enzyme RNase H to degrade the target mRNA and inhibit TNF-α protein synthesis at the transcriptional level. ISIS 104838 sodium induces moderate, self-limiting thrombocytopenia in cynomolgus monkeys. ISIS 104838 sodium can be used for the study of inflammatory diseases.
    ISIS 104838 sodium
  • HY-N1731
    2′-Hydroxy-5′-methoxyacetophenone
    		Inhibitor 99.96%
    2'-Hydroxy-5'-methoxyacetophenone is an acetophenone derivative with acaricidal activities. 2'-Hydroxy-5'-methoxyacetophenone attenuates the inflammatory response via NF-κB signaling pathway. 2'-Hydroxy-5'-methoxyacetophenone exhibits significant inhibitory activity against α-amylase, collagenase and aldose reductase (AR) with IC50s of 0.928, 3.264 and 20.046 μM, highlighting its potential in combating diabetes. 2'-Hydroxy-5'-methoxyacetophenone exhibits anti-ovarian cancer activity.
    2′-Hydroxy-5′-methoxyacetophenone
  • HY-13743
    Roquinimex
    		Inhibitor 99.69%
    Roquinimex (Linomide) is an orally active immunomodulator with antineoplastic, anti-inflammatory, and antiangiogenic activity. Roquinimex suppresses TH1 lymphocyte cytokines (IL-2, IFN-γ), promotes TH2 lymphocyte cytokines (IL-4, IL-10), increases NK cell, activated monocyte, and T cell activity. Roquinimex blocks macrophage TNF-α production and suppresses IL-1/IL-6 secretion. Roquinimex exhibits in vivo antitumour activity, suppresses rodent autoimmune disease signs, and ameliorates murine colitis and psoriasis. Roquinimex can be used for the research of leukemia, inflammatory bowel disease, multiple sclerosis, and psoriasis.
    Roquinimex
  • HY-175222
    GlcNAc-MurNAc
    		Inhibitor
    GlcNAc-MurNAc, a disaccharide, is a TLR4 agonist with a Kd of 383 μM for murine TLR4. GlcNAc-MurNAc directly binds to TLR4 and activates its downstream NF-κB and IRF pathways. GlcNAc-MurNAc improves Dextran sulfate sodium salt (DSS) (HY-116282C)-induced colitis in mice through a TLR4-dependent mechanism. GlcNAc-MurNAc can be used for the study of inflammatory bowel disease.
    GlcNAc-MurNAc
  • HY-P1825A
    TNF-α (10-36), human TFA
    		98.23%
    TNF-α (10-36), human (TFA) is a peptide of human TNF-α.
    TNF-α (10-36), human TFA
  • HY-W002199
    6:2 Fluorotelomer alcohol
    		Inhibitor 99.96%
    6:2 Fluorotelomer alcohol (6:2 FTOH) is an orally active, blood-brain barrier-permeable modulator of cyclin D1 and ETS1. 6:2 Fluorotelomer alcohol downregulates cyclin D1 expression, upregulates ETS1 via the TNF-α/ERK 1/2 pathway, impairs mitochondrial membrane potential and respiratory function, increases reactive oxygen species levels, disrupts calcium homeostasis and activates endoplasmic reticulum stress markers, and induces cell proliferation inhibition and endothelial-mesenchymal transition. Furthermore, 6:2 Fluorotelomer alcohol induces morphological abnormalities in zebrafish embryos and liver developmental damage, while disrupting the brain immune microenvironment in mice, causing systemic toxicity and delayed pup maturation in CD-1 mice. 6:2 Fluorotelomer alcohol also induces cortical neuron apoptosis, glial cell activation, synaptic abnormalities, colonic barrier damage, intestinal dysbiosis and autism spectrum disorder-like symptoms in mice. 6:2 Fluorotelomer alcohol shows no mutagenic, clastogenic, primary skin/eye irritation or skin sensitizing effects, exhibits no selective reproductive toxicity in CD-1 mice, and is classified as GHS Category 4 for acute oral toxicity. 6:2 Fluorotelomer alcohol can be used in studies of neurodevelopmental disorders and autism spectrum disorders.
    6:2 Fluorotelomer alcohol
  • HY-N7012
    7,3',4'-Tri-O-methylluteolin
    		Inhibitor 99.28%
    7,3',4'-Tri-O-methylluteolin (5-Hydroxy-3',4',7-trimethoxyflavone) is a flavonoid with multiple biological activities. 7,3',4'-Tri-O-methylluteolin inhibits soybean lipoxygenase (LOX), with an IC50 value of 23.97 µg/mL. 7,3',4'-Tri-O-methylluteolin possesses anti-inflammatory effects in Lipopolysaccharides (HY-D1056) (LPS)-induced RAW 264.7 macrophages. 7,3',4'-Tri-O-methylluteolin inhibits the binding of MDM2 with p53 and induces apoptosis in MCF-7 breast cancer cells. 7,3',4'-Tri-O-methylluteolin also has antioxidant, antifungal and antitrypanosomal activitiessup>[4]sup>[5].
    7,3',4'-Tri-O-methylluteolin
  • HY-P99669
    Iratumumab
    		Inhibitor 98.95%
    Iratumumab (MDX-060) a human anti-CD30 IgG1κ monoclonal antibody. Iratumumab inhibits the growth of CD30-expressing tumor cells. Iratumumab can be used for research of Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL).
    Iratumumab
  • HY-P99563
    Tibulizumab
    		Inhibitor 98.86%
    Tibulizumab (LY 3090106) is a tetravalent bispecific monoclonal antibody targeting B-cell activating factor (BAFF) and IL-17A with Kd values of 60 pM and 14 pM, respectively. Tibulizumab can be used for autoimmune disease research.
    Tibulizumab
  • HY-N1940
    β-Anhydroicaritin
    		Inhibitor 99.69%
    β-Anhydroicaritin is isolated from Boswellia carterii Birdware, has important biological and pharmacological effects, such as antiosteoporosis, estrogen regulation and antitumor properties. β-Anhydroicaritin ameliorates the degradation of periodontal tissue and inhibits the synthesis and secretion of TNF-α and MMP-3 in diabetic rats. β-Anhydroicaritin decreases the overproduction of NO, IL-10, TNF-α, MCP-1 and IL-6 in inperitonitis mice. β-Anhydroicaritin inhibits the elevation of intracellular Ca2+, and markedly decreases iNOS protein expression.
    β-Anhydroicaritin
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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