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-N0182R
    Fisetin (Standard)
    		Inhibitor
    Fisetin (Standard) is the analytical standard of Fisetin. This product is intended for research and analytical applications. Fisetin is a natural flavonol found in many fruits and vegetables with various benefits, such as antioxidant, anticancer, neuroprotection effects.
    Fisetin (Standard)
  • HY-10406
    Talmapimod
    		Inhibitor 98.68%
    Talmapimod (SCIO-469) is an orally active and selective inhibitor of p38α MAPK with an IC50 of 9 nM. Talmapimod inhibits the secretion of inflammatory factors (such as TNFα, IL-1β, IL-6, and VEGF) by suppressing the p38α MAPK pathway, and it also inhibits angiogenesis and osteoclast activation. Talmapimod inhibits the growth of multiple myeloma cells and induces apoptosis. Talmapimod can be used to study various hematological malignancies (such as multiple myeloma, myelodysplastic syndrome).
    Talmapimod
  • HY-P99742
    Mitazalimab
    		Inhibitor 99.23%
    Mitazalimab (ADC-1013; JNJ-64457107) is FcγR-dependent CD40 agonist with tumor-directed activity. Mitazalimab activates antigen-presenting cells, e.g. dendritic cells (DC), to initiate tumor-reactive T cells. Therefore, Mitazalimab induces tumor-specific T cells to infiltrate and kill tumors. Mitazalimab remodels the tumor-infiltrating myeloid microenvironment.
    Mitazalimab
  • HY-30235A
    Benzydamine hydrochloride
    		Inhibitor 99.21%
    Benzydamine hydrochloride is an orally administered prostaglandin synthesis inhibitor that has anti-inflammatory, analgesic, antipyretic, and antibacterial properties. Benzydamine hydrochloride can inhibit TNF-α, stabilize cell membranes, and reduce oxidative stress within cells.
    Benzydamine hydrochloride
  • HY-110247
    TRAF-STOP inhibitor 6877002
    		Inhibitor 99.67%
    TRAF-STOP inhibitor 6877002 is a selective CD40-TRAF6 interaction inhibitor. TRAF-STOP inhibitor 6877002 exerts anti-atherosclerotic activity by blocking the CD40-TRAF6 signaling pathway, inhibiting classical monocyte activation, leukocyte recruitment, and macrophage activation and migration. TRAF-STOP inhibitor 6877002 reduces the phosphorylation levels of signaling intermediates in the canonical NF-κB pathway.
    TRAF-STOP inhibitor 6877002
  • HY-N9965
    2'-Fucosyllactose
    		Inhibitor 99.97%
    2'-Fucosyllactose (2'-FL) is an oligosaccharide that could be derived from human milk. 2'-Fucosyllactose regulates the expression of CD14, alleviates colitis and regulates the gut microbiome. 2'-Fucosyllactose stimulates T cells to increase IFN-γ production and decreases IL-6, IL-17, and TNF-α production of cytokines.
    2'-Fucosyllactose
  • HY-P990794
    Anti-Mouse TNF-alpha/TNFSF2 Antibody (XT3.11)
    		Inhibitor 98.19%
    Anti-Mouse TNF-alpha/TNFSF2 Antibody (XT3.11) is a rat-derived IgG1 antibody inhibitor, targeting to TNF-alpha/TNFSF2. Anti-Mouse TNF-alpha/TNFSF2 Antibody (XT3.11) neutralizes of TNF-alpha. Anti-Mouse TNF-alpha/TNFSF2 Antibody (XT3.11) can be used for the researches of cancer, infection and immunology, such as dengue virus and B16K1 tumor.
    Anti-Mouse TNF-alpha/TNFSF2 Antibody (XT3.11)
  • HY-N0481
    Roburic acid
    		Inhibitor 99.93%
    Roburic acid acts as an anti-inflammatory, anti-tumor and osteoclastogenesis inhibitor, with a Ki of 7.066 μM against human TNF, an IC50 of 9 μM against human COX-2, and an IC50 of 5 μM against ovine COX-1. Roburic acid reduces the production of inflammatory mediators such as NO and IL-6 in macrophages by inhibiting the NF-κB and MAPK (p38/JNK) pathways. By competitively inhibiting the TNF-TNF-R1 interaction, Roburic acid blocks the downstream NF-κB signaling pathway, thereby inducing cell cycle arrest and apoptosis in cancer cells. Roburic acid specifically inhibits osteoclastogenesis and bone resorption by suppressing the RANKL/TRAF6/NF-κB/NFATc1 axis. Roburic acid can be used in research related to osteolytic diseases such as osteoporosis, colorectal cancer and inflammatory diseases.
    Roburic acid
  • HY-P990070
    Zigakibart
    		Inhibitor 99.30%
    Zigakibart (BION-1301) is an IgG4-kappa, humanized monoclonal antibody against TNFSF13 (tumor necrosis factor (TNF) superfamily member 13, APRIL, CD256). Zigakibart exhibits anti-inflammatory activity.
    Zigakibart
  • HY-W011404
    Tributyrin
    		Inhibitor 98.91%
    Tributyrin (Glyceryl tributyrate), a neutral short-chain fatty acid triglyceride, is a stable and rapidly absorbed proagent of Butyric Acid. Tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing effective butyrate directly into the cell in vivo. Tributyrin has potent antiproliferative, proapoptotic and differentiation-inducing effects.
    Tributyrin
  • HY-P99670
    Iscalimab
    		Inhibitor 99.64%
    Iscalimab (CFZ-533) is a non-depleting IGg1 monoclonal antibody targeting CD40 (KD: 0.3 nM). Iscalimab can be used for research of Graves' hyperthyroidism and autoimmune diseases.
    Iscalimab
  • HY-N0152
    Myricitrin
    		Inhibitor 99.76%
    Myricitrin, a naturally occurring flavonoid, is an orally active nitric oxide (NO) and PKC inhibitor. Myricitrin has central nervous system activity, including anxiolytic-like action. Myricitrin possesses antioxidant, anti-inflammatory, antifibrotic and anti-malarial effects.
    Myricitrin
  • HY-P990151
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6)
    		Inhibitor
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6) is an anti-mouse TL1A/TNFSF15 IgG monoclonal antibody. Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6) can reduce TL1A levels and block TL1A-DR3 interactions. Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6) can be used for research on inflammation conditions such as colitis and collagen-induced arthritis (CIA).
    Anti-Mouse TL1A/TNFSF15 Antibody (5G4.6)
  • HY-N3021
    D-chiro-Inositol
    		Inhibitor 98.0%
    D-chiro-Inositol is a stereoisomer of inositol that exhibits activities such as improving glucose metabolism, anti-tumor effects, anti-inflammatory properties, and antioxidant activity. D-chiro-Inositol effectively alleviates cholestasis by enhancing bile acid secretion and reducing oxidative stress. D-chiro-Inositol improves insulin resistance, lowers hyperglycemia and circulating insulin levels, reduces serum androgen levels, and ameliorates some metabolic abnormalities associated with X syndrome by mimicking the action of insulin. Additionally, D-chiro-Inositol can induce a reduction in pro-inflammatory factors (such as Nf-κB) and cytokines (such as TNF-α), thereby exerting anti-inflammatory effects. D-chiro-Inositol may be used in the study of liver cirrhosis, breast cancer, type 2 diabetes, and polycystic ovary syndrome.
    D-chiro-Inositol
  • HY-12557
    γ-Glutamylvaline
    		Inhibitor 99.94%
    γ‑Glutamylvaline (γ-Glu-Val) is a calcium‑sensing receptor (CaSR) agonist. γ‑Glutamylvaline activates CaSR and facilitates its binding to β‑arrestin 2 to modulate inflammatory and metabolic homeostasis signaling. γ‑Glutamylvaline inhibits TNF‑α‑induced IL‑6/MCP‑1 and enhances adiponectin/PPARγ in adipocytes. γ‑Glutamylvaline upregulates Wnt5a, restores β‑catenin phosphorylation, and reduces serine‑phosphorylated IRS‑1 in adipocytes. γ-Glutamylvaline can be used for the research of low-grade chronic inflammation.
    γ-Glutamylvaline
  • 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-P99361
    Enavatuzumab
    		Inhibitor 98.27%
    Enavatuzumab (PDL192; ABT-361) is a humanized IgG1 monoclonal antibody targeting the receptor of TNF-like weak inducer of apoptosis (TWEAK). TWEAK (Fn14; TNFRSF12A), the natural ligand of the TWEAK receptor (TweakR), stimulates multiple cellular responses. Enavatuzumab induces tumor growth inhibition through direct TweakR signaling and antibody dependent cell-mediated cytotoxicity (ADCC). Enavatuzumab can actively recruits and activates myeloid effectors to kill tumor cells. Enavatuzumab inhibits the growth of various human TweakR-positive cancer cell lines and xenografts in vitro and in vivo .
    Enavatuzumab
  • HY-W016412
    Coenzyme Q0
    		Inhibitor 99.79%
    Coenzyme Q0 (CoQ0) is a potent, oral active ubiquinone compound can be derived from Antrodia cinnamomea. Coenzyme Q0 induces apoptosis and autophagy, suppresses of HER-2/AKT/mTOR signaling to potentiate the apoptosis and autophagy mechanisms. Coenzyme Q0 regulates NFκB/AP-1 activation and enhances Nrf2 stabilization in attenuation of inflammation and redox imbalance. Coenzyme Q0 has anti-angiogenic activity through downregulation of MMP-9/NF-κB and upregulation of HO-1 signaling.
    Coenzyme Q0
  • HY-N1949
    Homoplantaginin
    		Inhibitor 99.70%
    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-114360A
    Taurohyodeoxycholic acid sodium
    		Inhibitor 99.99%
    Taurohyodeoxycholic acid (THDCA) sodium is the taurine-conjugated form of the secondary bile acid hyodeoxycholic acid. Taurohyodeoxycholic acid can also reduce the activity and expression of myeloperoxidase TNF-α and IL-6, as well as colonic damage in TNBS-induced ulcerative colitis mouse model.
    Taurohyodeoxycholic acid sodium
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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