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-15643A
    LY 303511 hydrochloride
    		Activator 98.87%
    LY 303511 hydrochloride 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 hydrochloride
  • HY-W753791
    (±)-Perillaldehyde
    		Inhibitor
    (±)-Perillaldehyde has an antidepressant effect by modulating the olfactory nervous system in a mouse model of stress-induced depression. (±)-Perillaldehyde also has anti-inflammatory activity, inducing JNK activation in RAW264.7 cells and inhibiting the expression of TNF-α, with an IC50 of 171.7 μM.
    (±)-Perillaldehyde
  • HY-P99393
    Tavolixizumab
    		Inhibitor 99.66%
    Tavolixizumab (MEDI 0562; Tavolimab) is a human monoclonal antibody to TNFRSF4 (TNF receptor superfamily member 4) for use in cancer immunology research.
    Tavolixizumab
  • HY-P99605
    Cinrebafusp alfa
    		Inhibitor 98.53%
    Cinrebafusp alfa (PRS 343) is a high affinity CD137/HER2 bispecfic anticalin-based drug. Cinrebafusp alfa binds to recombinant human HER2 (Kd=0.3 nM) and human monomeric CD137 (4-1BB; Kd=5 nM). Cinrebafusp alfa facilitates T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation, further enhancing T-cell receptor-mediated activity and leading to tumor destruction. Cinrebafusp alfa has the potential for HER2+ solid tumors research.
    Cinrebafusp alfa
  • HY-168894
    CT-1
    		Inhibitor 99.90%
    CT-1 is a secreted protein belonging to the IL-6 cytokine family. Overexpression of CT-1 enhances cell proliferation, migration and angiogenesis via the ADMA/DDAH pathway. CT-1 inhibits the growth of triple-negative breast cancer cells by simultaneously inducing Ferroptosis in N2-type tumor-associated neutrophils and cancer cells. CT-1 activates the Jak/STAT-3, p42/p44 MAPK and AMPK pathways, and inhibits GSK-3β activity through phosphorylation to induce cardiomyocyte hypertrophy. CT-1 enhances the viability of cardiomyocytes and neurons, reduces cell Apoptosis, induces the expression of heat shock proteins (HSP) and BNP, and inhibits TNF levels. CT-1 exerts anti-tumor activity in mouse models of triple-negative breast cancer. CT-1 improves cognitive impairment in mice. CT-1 is applicable to the research of ischemic heart disease, triple-negative breast cancer, myocardial hypertrophy, Parkinson's disease, hypertensive heart disease, myocardial infarction, acute Chagas cardiomyopathy, high-fat diet-induced cognitive impairment and diabetes-related cognitive impairment.
    CT-1
  • HY-154822
    DRI-C25441
    		Inhibitor 99.53%
    DRI-C25441 is a potent blocker of CD40 and CD40L interaction, with an IC50 of 0.36 μM. DRI-C25441 can inhibit the immune response induced by alloantigen. can inhibit CD40L induced activation of NF-κB signaling pathway. DRI-C25441 commonly is used in research on immune conditions .
    DRI-C25441
  • HY-N0358
    1,4-Dicaffeoylquinic acid
    		Inhibitor 99.25%
    1,4-Dicaffeoylquinic acid (1,4-DCQA) is a phenylpropanoid compound that can be isolated from Xanthii fructus and an inhibitor of xanthine oxidase (IC50: 7.36 μM). 1,4-Dicaffeoylquinic acid has anti-inflammatory activity and can inhibit the production of TNF-α induced by LPS (HY-D1056).
    1,4-Dicaffeoylquinic acid
  • HY-N7513
    Homovanillyl alcohol
    		99.84%
    Homovanillyl alcohol is a biological metabolite of Hydroxytyrosol. Hydroxytyrosol is a phenolic compound that is present in virgin olive oil (VOO) and wine. Homovanillyl alcohol protects red blood cells (RBCs) from oxidative injury and has protective effect on cardiovascular disease.
    Homovanillyl alcohol
  • HY-173425
    STING-IN-15
    		Inhibitor 99.04%
    STING-IN-15 is an orally active STING inhibitor, with an IC50 of 116 nM against h-STING and an IC50 of 96.3 nM against m-STING. STING-IN-15 inhibits the STING signaling pathway in cells, reduces the secretion of IFN-β and IP-10, downregulates the expression of ISG15, ISG56 and TNF-α, and suppresses the phosphorylation of TBK1/IRF3. STING-IN-15 alleviates systemic and renal inflammation induced by STING agonists in mice, reduces tissue damage and the expression of interferon pathway genes, and inhibits spontaneous tissue inflammation in mice. STING-IN-15 can be used for the research of acute kidney injury and autoimmune/inflammatory diseases.
    STING-IN-15
  • HY-159884
    MG-T-19
    		Activator 98.34%
    MG-T-19 is an effective TIM-3 inhibitor that can suppress the interaction of TIM-3 with PtdSer, CEACAM1, and Gal-9. MG-T-19 can increase the production of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in peripheral blood mononuclear cells (PBMCs) from healthy donors, and enhance the ability of PBMCs to inhibit the proliferation of Kasumi-1 cells (an acute myelogenous leukemia cell line).
    MG-T-19
  • HY-12642
    Diethylcarbamazine citrate
    		98.01%
    Diethylcarbamazine citrate is an orally active microfilaricidal agent used originally in onchocerciasis and lymphatic filiariasis. Diethylcarbamazine citrate reduces eosinophil trafficking to the lung tissue and exerts anti-allergic effects. Diethylcarbamazine citrate reduces serum levels of leptin, TNF-α, IL-6, MCP-1, glucose, insulin, and triglycerides, and ameliorates insulin resistance without altering body, liver, or adipose tissue weights. Diethylcarbamazine citrate enhances reactive oxygen intermediate expression by polymorphonuclear neutrophils, increases lymphocyte proliferation, and inhibits actinomycetoma lesion development. Diethylcarbamazine citrate can be used for the researches of bronchial asthma, insulin resistance and infection.
    Diethylcarbamazine citrate
  • HY-P99940
    Remtolumab
    		Inhibitor 99.24%
    Remtolumab is a bispecific variable domain immunoglobulin molecule with human affinities for TNFα and IL-17 in the low pM range of Kd. Remtolumab can be used in research related to rheumatoid arthritis, psoriatic arthritis, and moderate-to-severe plaque psoriasis.
    Remtolumab
  • HY-P2612
    WP9QY
    		Antagonist 99.78%
    WP9QY is an inhibitor targeting TNFα and RANKL, which blocks the TNFα-TNFR1 interaction and inhibits TNFα-mediated apoptosis, cytotoxicity and bone destruction. WP9QY inhibits osteoclastogenesis and promotes osteoblast differentiation, induces chondrocyte proliferation and glycosaminoglycan production, and synergizes with TGF-β3 to promote chondrogenesis. WP9QY effectively repairs full-thickness articular cartilage defects in rabbits via intra-articular injection, and inhibits methylmercury-induced reduction of NeuN-positive cells in mouse brain slices. WP9QY can be applied to the research of diseases related to methylmercury-induced neuronal death, cartilage injury, osteoarthritis and bone loss.
    WP9QY
  • HY-15507
    VGX-1027
    		Inhibitor 99.67%
    VGX-1027 is an orally active isoxazole compound that exhibits various immunomodulatory properties. VGX-1027 targets macrophages, reducing the production of the proinflammatory mediators TNF-α, IL-1β, IL-10. VGX-1027 has antidiabetogenic effects by limiting cytokine-mediated immunoinflammatory events.
    VGX-1027
  • HY-P3585
    Epobis
    		Inhibitor 99.38%
    Epobis, a dendrimeric peptide, is a recombinant form of erythropoietin. Epobis is a potent erythropoietin receptor agonist. Epobis promotes neuritogenesis in primary motoneurons. Epobis decrease TNF release and crosses the blood-brain barrier. Epobis has anti-inflammatory and memory enhancing properties.
    Epobis
  • HY-P9980A
    Belantamab (FUT8-KO)
    		98.10%
    Belantamab (FUT8-KO) is an anti-BCMA (TNFRSF17) monoclonal antibody expressed by CHO cells with the fucosyltransferase 8 gene (FUT8) knocked out. Fucose deficiency enhances the ADCC effect of the antibody. Belantamab (FUT8-KO) can be used to synthesize antibody-active molecule conjugate (ADC), Belantamab mafodotin.
    Belantamab (FUT8-KO)
  • HY-W015515
    L-Citronellol
    		Inhibitor 99.92%
    L-Citronellol ((S)-3,7-Dimethyloct-6-en-1-ol) is a natural product with anti-allergic and neuroprotective effects. L-Citronellol inhibits mast cell activation and the release of inflammatory factors by inhibiting the ERK pathway. L-Citronellol inhibits BACE1/PSEN1 and AChE, reduces TNF-α expression and lipid peroxidation, demonstrating the potential of multi-target anti-Alzheimer's disease (AD).
    L-Citronellol
  • HY-P991052
    GSK-3174998
    		Inhibitor ≥99.0%
    GSK-3174998 is a humanized IgG1 OX40/TNFRSF4 agonistic monoclonal antibody. GSK-3174998 has the potential for the study of advanced solid tumors. The isotype control for GSK-3174998 can refer to Human IgG1 kappa, Isotype Control (HY-P99001).
    GSK-3174998
  • HY-B0113R
    Omeprazole (Standard)
    Omeprazole (Standard) is the analytical standard of Omeprazole. This product is intended for research and analytical applications. Omeprazole (H 16868) is an orally active H+,K+-ATPase inhibitor and a proton pump inhibitor. Omeprazole competitively inhibits CYP2C19, CYP3A4, and CYP2C9 activity. Omeprazole inhibits gastric acid secretion and can be used for acid-related gastrointestinal disorders. Omeprazole inhibits pancreatic cancer cell proliferation, induces apoptosis, autophagosome accumulation (elevated LC3-I and LC3-II levels), oxidative stress, and cytogenetic imbalance, modulates lysosomal transport, reduces inflammatory cytokines. Omeprazole alters small intestinal morphology and magnesium absorption, and induces gastric mucosa morphologic changes. Omeprazole aslo has neuroprotective and antibacterial effects.
    Omeprazole (Standard)
  • HY-107352
    Fosfenopril
    		Inhibitor 99.85%
    Fosfenopril (Fosinoprilat) is a potent angiotensin converting enzyme (ACE) inhibitor. Fosfenopril alleviates lipopolysaccharide (LPS)-induced inflammation by inhibiting TLR4/NF-κB signaling in monocytes.
    Fosfenopril
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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