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-133122
    UCB-9260
    		Inhibitor 99.96%
    UCB-9260, an orally active compound, inhibits TNF signaling by stabilising an asymmetric form of the trimer. UCB-9260 is selective for TNF over other superfamily members, and binds TNF with a similar Kd of 13 nM.
    UCB-9260
  • HY-P1860
    TNF-α (31-45), human
    		Activator 99.77%
    TNF-α (31-45), human is a potent NF-kB pathway activator. TNF-αis a proinflammatory cytokine that induces necrosis or apoptosis. TNF alpha stimulates NF-κB pathway via TNFR2 promotes cancer growth, invasion, and metastasis.
    TNF-α (31-45), human
  • HY-N0633
    Muscone
    		Inhibitor ≥98.0%
    Muscone is the main active monomer of traditional Chinese medicine musk. Muscone inhibits NF-κB and NLRP3 inflammasome activation. Muscone remarkably decreases the levels of inflammatory cytokines (IL-1β, TNF-α and IL-6), and ultimately improves cardiac function and survival rate.
    Muscone
  • HY-N0201
    Atractylenolide I
    		99.94%
    Atractylenolide I is a sesquiterpene derived from the rhizome of Atractylodes macrocephala, possesses diverse bioactivities, such as neuroprotective, anti-allergic, anti-inflammatory and anticancer properties. Atractylenolide I reduces protein levels of phosphorylated JAK2 and STAT3 in A375 cells, and acts as a TLR4-antagonizing agent.
    Atractylenolide I
  • HY-P9953
    Certolizumab pegol
    		Inhibitor 99.30%
    Certolizumab pegol (Certolizumab) is a recombinant, polyethylene glycolylated, antigen-binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor-α (TNF-α). Certolizumab pegol can be used for rheumatoid arthritis and Crohn disease research.
    Certolizumab pegol
  • HY-126360
    Oxazolone
    		Activator ≥98.0%
    Oxazolone is a haptenizing agent that induces acute or chronic inflammation of the large intestine and is used to construct models of colitis. Oxazolone can cause Th1/Th2-dependent colitis with weight loss and diarrhea. Oxazolone-induced inflammation can be mitigated by neutralizing anti-IL-4 or anti-TNF-α antibodies or decoy IL-13R2-α-FC proteins.
    Oxazolone
  • HY-B0539
    Desloratadine
    		Inhibitor 99.83%
    Desloratadine (Sch34117) is an orally active and selective H1 receptor antagonist (Ki=0.9 nM) with anti-inflammatory and anti-allergic activities. Desloratadine inhibits the release of histamine and LTC4 from human basophils and targets the regulatory signals of IL-4 and IL-13 production in basophils. Desloratadine significantly alleviates SAR symptoms in patients with concurrent asthma and can be used in the study of seasonal allergic rhinitis and chronic idiopathic urticaria.
    Desloratadine
  • HY-N0029
    Forsythoside B
    		99.99%
    Forsythoside B is a phenylethanoid glycoside isolated from Forsythia suspensa (Thunb.) Vahl, a Chinese folk medicinal plant for treating inflammatory diseases and promoting blood circulation. Forsythoside B could inhibit TNF-alpha, IL-6, IκB and modulate NF-κB.
    Forsythoside B
  • HY-116522
    AR420626
    		98.29%
    AR420626 is a selective agonist of free fatty acid receptor 3 (FFAR3) (IC50=117 nM). AR420626 has anti-inflammatory, anticancer and antidiabetic activities. AR420626 improves neurogenic diarrhea by inhibiting nAChR mediated neural pathways. AR420626 inhibits the growth of HepG2 xenografts and inhibits the proliferation of hepatoma cells by inducing apoptosis. AR420626 also suppresses allergic asthma and eczema and has the ability to activate GPR41 to increase Ca2+ signal-mediated glucose uptake and improve diabetes.
    AR420626
  • HY-N0297
    Sinensetin
    		Inhibitor 99.87%
    Sinensetin is a methylated flavonoid found in fruits that has strong anti-vascular and anti-inflammatory properties.
    Sinensetin
  • HY-P9952
    Belimumab
    		Inhibitor 99.40%
    Belimumab (LymphoStat B) is a humanized IgG1λ monoclonal antibody against B-lymphocyte stimulator (BLyS) protein. Belimumab antagonizes BLyS activity in autoimmune diseases and B-lymphocyte malignancies. Belimumab can be used for systemic lupus erythematosus (SLE) research.
    Belimumab
  • HY-P99056
    Utomilumab
    		Inhibitor
    Utomilumab (PF 05082566) is a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137. Utomilumab can be used for the research of relapsed/refractory follicular lymphoma (FL) and other CD20+ non-Hodgkin lymphomas (NHL).
    Utomilumab
  • HY-N6796
    Manumycin A
    		Inhibitor 99.27%
    Manumycin A is a polyketide antibiotic and an inhibitor of thioredoxin reductase 1 (TrxR-1). Manumycin A can inhibit the growth of breast cancer cells and exert its anti-tumor activity through LC3. Manumycin A can downregulate the release of pro-inflammatory cytokines in human monocytes stimulated by TNF α, and has potential anti-inflammatory activity. Manumycin A can inhibit the Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration resistant prostate cancer cells to suppress exosome biogenesis and secretion.
    Manumycin A
  • HY-134471
    TNF-α-IN-2
    		Inhibitor 98.75%
    TNF-α-IN-2 is a potent and orally active inhibitor of tumor necrosis factor alpha (TNFα), with an IC50 of 25 nM in the HTRF assay. TNF-α-IN-2 distorts the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNFR1. TNF-α-IN-2 can be used for the research of rheumatoid arthritis.
    TNF-α-IN-2
  • HY-122663A
    BIO8898
    		Inhibitor 99.88%
    BIO8898 is a potent CD40-CD154 inhibitor. BIO8898 inhibits soluble CD40L binding to CD40-Ig with an IC50 value of 25 µM. BIO8898 inhibits CD40L-induced apoptosis.
    BIO8898
  • HY-N0509
    Astilbin
    		Inhibitor 99.97%
    Astilbin is a flavonoid compound and enhances NRF2 activation. Astilbin also suppresses TNF-α expression and NF-κB activation.
    Astilbin
  • HY-107737
    1,2-DLPC
    		Activator ≥98.0%
    1,2-DLPC (1,2-Dilauroyl-sn-glycero-3-phosphocholine) is a ligand for LRH-1 agonists. 1,2-DLPC is a phospholipid used in the synthesis of liposomes. 1,2-DLPC enhances fat breakdown and apoptosis in fat cells through a TNFα-dependent pathway, while also inhibiting palmitate-induced insulin resistance through PPARα-mediated inflammation in muscle cells.
    1,2-DLPC
  • HY-P9980
    Belantamab
    		Inhibitor 99.62%
    Belantamab (GSK2857914) is a humanised IgG1 anti-BCMA (TNFRSF17) monoclonal antibody. Belantamab can be used in the synthesis of antibody-drug conjugate (ADC), Belantamab mafodotin.
    Belantamab
  • HY-N0472
    Geraniin
    		Inhibitor 99.84%
    Geraniin is a TNF-α releasing inhibitor with numerous activities including anticancer, anti-inflammatory, and anti-hyperglycemic activities, with an IC50 of 43 μM.
    Geraniin
  • HY-147141
    HS-276
    		Inhibitor 98.59%
    HS-276 is an orally active, potent and highly selective TAK1 inhibitor, with a Ki of 2.5 nM. HS-276 shows significant inhibition of TAK1, CLK2, GCK, ULK2, MAP4K5, IRAK1, NUAK, CSNK1G2, CAMKKβ-1, and MLK1, with IC50 values of 8.25, 29, 33, 63, 125, 264, 270, 810, 1280, and 5585 nM, respectively. HS-276 can be used for rheumatoid arthritis (RA) research.
    HS-276
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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