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-156817
    TNIK-IN-6
    		Inhibitor 98.28%
    TNIK-IN-6 (Compound 9) is an inhibitor of Traf2 and Nck-interacting kinase (TNIK) and , with IC50 of 0.93 μM, that plays important roles in neurological and psychiatric disorders.
    TNIK-IN-6
  • HY-N12188
    Stigmasta-3,5-dien-7-one
    		Inhibitor 99.84%
    Stigmasta-3,5-dien-7-one is a steroid compound that can be isolated from Harrisonia abyssinica. Stigmasta-3,5-dien-7-one blocks the NF-κB signaling pathway via down-regulation of phospho-p38 mitogen-activated protein kinase and phosphorylation and degradation of inhibitor of NF-κB α. Stigmasta-3,5-dien-7-one reduces LPS (HY-D1056)-induced nitric oxide, PGE2, and pro-inflammatory cytokine levels in macrophages. Stigmasta-3,5-dien-7-one can be used for inflammation diseases.
    Stigmasta-3,5-dien-7-one
  • HY-172590
    LZ-07
    		Inhibitor 98.27%
    LZ-07 is a IRAK4 PROTAC degrader (DC50 = 1.14 nM). LZ-07 leads to marked suppression of cytokines including IL-6, IL-1β, TNF-α, and IL-10 upon degradation of IRAK4. LZ-07 can be studied in research for autoimmune diseases (Pink: IRAK4 ligand (HY-172591); Blue: CRBN ligand (HY-34590); Black: linker (HY-B0149); CRBN ligand + linker: HY-172593).
    LZ-07
  • HY-N0136A
    (±)-Taxifolin
    		99.34%
    (±)-Taxifolin ((±)-Dihydroquercetin) is the racemate of Taxifolin (HY-N0136). Taxifolin exhibits important anti-tyrosinase activity. Taxifolin exhibits significant inhibitory activity against collagenase with an IC50 value of 193.3 μM. Taxifolin is an important natural compound with antifibrotic activity. Taxifolin is a free radical scavenger with antioxidant capacity.
    (±)-Taxifolin
  • HY-P991570
    Zaptuzumab
    		Inhibitor 99.0%
    Zaptuzumab (AD5-10) is a DR5-specific humanized monoclonal antibody that selectively binds to DR5 with high affinity. Zaptuzumab specifically induces cancer cell death by both caspase-apoptosis and autophagic cell death (ACD). Zaptuzumab activates both ADCC and CDC. Zaptuzumab induces ROS generation and GSH level reduction. Zaptuzumab shows a significant suppression of the tumor growth and good safety in various xenografts mice tumor models.
    Zaptuzumab
  • HY-111326
    Naphazoline
    		Inhibitor 99.74%
    Naphazoline (Naphthazoline) is a potent α-adrenergic receptor agonist. Naphazoline reduces vascular hyperpermeability and promotes vasoconstriction. Naphazoline reduces the levels of inflammatory factors (TNF-α, IL-1β and IL-6), cytokines (IFN-γ and IL-4), IgE, GMCSF, and NGF. Naphazoline can be used for non-bacterial conjunctivitis research.
    Naphazoline
  • HY-B1272AS
    Desipramine-d4
    		98.93%
    Desipramine-d4 is the deuterium labeled Desipramine (HY-B1272A). Desipramine is a first-generation tricyclic antidepressant. Desipramine selectively binds to norepinephrine transporter and blocks neuronal norepinephrine reuptake. Desipramine activates MAPK signaling via ERK1/2, JNK, and p38, represses NF-κB and AP-1 activity, and induces apoptosis via ROS elevation, mitochondrial membrane potential reduction, and intracellular calcium increase. Desipramine also shows anyi-inflammatory activity, inhibiting TNF-α production. Desipramine can be used for the research of hepatocellular cancer, inflammation, and neurological diseases.
    Desipramine-d<sub>4</sub>
  • HY-P991179
    MK-4166
    		Agonist 98.20%
    MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. MK-4166 enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes.
    MK-4166
  • HY-176785S
    MCB-294
    		Agonist
    MCB-294 is a dual-state pan-KRAS inhibitor that selectively inhibits KRAS over NRAS and HRAS. MCB-294 capable of binding both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS with Kds of approximately 1 pM and 10 nM, respectively. MCB-294 broadly impairs the growth of hTERT-HPNE cells expressing G12D, G12C, G12V, G12S, G13D, and wild-type KRAS, with IC50s of approximately 700 nM. MCB-294 induces irreversible apoptosis in KRAS-mutated tumors. MCB-294 effectively suppress KRASG12C inhibitor-resistant cancer cells and remodel the tumor immune microenvironment. MCB-294 can be used for the study of pancreatic cancer, colorectal cancer and lung cancer.
    MCB-294
  • HY-133807A
    (Rac)-Benpyrine
    		Inhibitor 99.30%
    (Rac)-Benpyrine, a racemate of Benpyrine, is a potent and orally active TNF-α inhibitor. (Rac)-Benpyrine has the potential for TNF-α mediated inflammatory and autoimmune disease research.
    (Rac)-Benpyrine
  • HY-P99821
    Ravagalimab
    		Inhibitor 99.31%
    Ravagalimab (ABBV-323) is a CD40 antagonist (EC50: 3.7 nM). Ravagalimab can be used for research of Crohn's disease.
    Ravagalimab
  • HY-P99057A
    Varlilumab (anti-CD27)
    		Inhibitor 99.68%
    Varlilumab (CDX-1127) (anti-CD27) is an agonist anti-CD27 monoclonal antibody. Varlilumab (anti-CD27) can promote T cell expansion and activate the immune response. Varlilumab (anti-CD27) has anti-tumor activity and can be used in the research of hematological malignancies and solid tumors.
    Varlilumab (anti-CD27)
  • HY-P99470
    Benufutamab
    		Agonist 98.62%
    Benufutamab (GEN1029) is a death receptor 5 (DR5)-specific agonistic antibody. Benufutamab is a mixture of 2 noncompeting DR5-specific IgG1 antibodies, each with an E430G mutation in the Fc domain. Benufutamab has antitumor effects.
    Benufutamab
  • HY-P99321
    Teneliximab
    		Inhibitor ≥99.0%
    Teneliximab (BMS-224819) is a chimeric monoclonal antibody, blocks the CD40-CD40L interaction. Teneliximab (BMS-224819) has partial agonist activity resulting in some signaling through CD40 and peripheral B cell depletion.
    Teneliximab
  • HY-N8884
    Coelonin
    		Inhibitor 98.0%
    Coelonin is a dihydrophenanthrene with anti-inflammation activity. Coelonin inhibits LPS-induced PTEN phosphorylation. Coelonin inhibits NF-κB activation and p27Kip1 degradation by regulating the PI3K/AKT pathway negatively. Coelonin can inhibit IκBα phosphorylation and degradation and increases the expression of IκBα protein.
    Coelonin
  • HY-100573S
    Necrosulfonamide-d4
    		Inhibitor 99.65%
    Necrosulfonamide-d4 is the deuterium labeled Necrosulfonamide (HY-100573). Necrosulfonamide is a MLKL and Gasdermin D (GSDMD) inhibitor, capable of separately inhibiting necroptosis and pyroptosis of cells. Necrosulfonamide does not affect the activation of upstream signals, but specifically inhibits the downstream executor oligomerization step. Necrosulfonamide reduces the expression of the key kinases NLRP3 and caspase-1 involved in necroptosis and pyroptosis, activate the Nrf2 pathway and the downstream antioxidant enzymes, and also downregulates a variety of inflammatory factors. Necrosulfonamide plays significant roles in various diseases such as neurodegenerative diseases (such as Parkinson’s disease), tissue damage and ischemia-reperfusion injury, inflammatory bowel disease, osteoarthritis and fracture repair, and hair loss by regulating two important programmed necrosis pathways.
    Necrosulfonamide-d<sub>4</sub>
  • HY-145726
    ISIS 104838
    		Inhibitor
    ISIS 104838 is an antisense oligonucleotide targeting TNF-α. ISIS 104838 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 induces moderate, self-limiting thrombocytopenia in cynomolgus monkeys. ISIS 104838 can be used for the study of inflammatory diseases.
    ISIS 104838
  • HY-101170
    BU224 hydrochloride
    		Inhibitor
    BU224 hydrochloride is a selective and high affinity imidazoline I2 receptor ligand, with a Ki of 2.1 nM. BU224 hydrochloride is sometimes used as an I2 receptor antagonist. BU224 hydrochloride exerts neuroprotective effects, with anti-inflammatory and anti-apoptotic properties. BU224 hydrochloride improves memory in 5XFAD mice, enlarging dendritic spines and reducing Aβ-induced changes in NMDARs. BU224 hydrochloride can be used for Alzheimer's disease research.
    BU224 hydrochloride
  • HY-B0026
    Ceftiofur hydrochloride
    		Inhibitor 98.43%
    Ceftiofur hydrochloride is a cell wall synthesis inhibitor that targets bacterial penicillin-binding proteins (PBPs) and has anti-inflammatory effects in endotoxemia. Ceftiofur hydrochloride exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycan, leading to bacterial cell lysis. Ceftiofur hydrochloride 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 hydrochloride
  • HY-P990686
    Ispectamab
    		98.102%
    Ispectamab is an anti-TNFRSF17 human IgG1 κ monoclonal antibody. Recommend Isotype Controls: Human IgG1 kappa, Isotype Control (HY-P99001).
    Ispectamab
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. 
 

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