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-138063
    Siegeskaurolic acid
    		Inhibitor
    Siegeskaurolic acid is an orally active anti-inflammatory agent. Siegeskaurolic acid inhibits the productions of nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha) and the activationon of nuclear factor-kappaB .
    Siegeskaurolic acid
  • HY-101849R
    Fasentin (Standard)
    		Agonist
    Fasentin (Standard) is the analytical standard of Fasentin. This product is intended for research and analytical applications. Fasentin, a potent glucose uptake inhibitor, inhibits GLUT-1/GLUT-4 transporters. Fasentin preferentially inhibits GLUT4 (IC50=68 μM) over GLUT1. Fasentin is a death receptor stimuli (FAS) sensitizer and sensitizes cells to FAS-induced cell death. Fasentin is also a tumor necrosis factor (TNF) apoptosis-inducing ligand sensitizer. Fasentin blocks glucose uptake in cancer cell lines and has anti-angiogenic activity.
    Fasentin (Standard)
  • HY-100176R
    PF-4878691 (Standard)
    PF-4878691 (Standard) is the analytical standard of PF-4878691. This product is intended for research and analytical applications. PF-4878691 (3M-852A) is an orally active TLR7 agonist. PF-4878691 has the innate immune response activity, antiviral efficacy against HCV, and can be used for the research of cancer.
    PF-4878691 (Standard)
  • HY-N15347
    Talaromyketide B
    		Inhibitor
    Talaromyketide B is a polyketide compound with anti-inflammatory activity, discovered in the soil bacterium Talaromyces sp. KYS-41. Talaromyketide B inhibits the activation of the NF-κB and MAPK signaling pathways and dose-dependently suppresses pro-inflammatory cytokines, such as IL-1β, IL-6, IL-10, and TNF-α, as well as the transcriptional activity of inflammatory mediators, including iNOS and COX-2. Talaromyketide B holds potential for research in the fields of immunity and inflammatory diseases.
    Talaromyketide B
  • HY-171591
    SIK2-IN-4
    		Inhibitor
    SIK2-IN-4 (Compound 4) is a highly selective SIK1/2 inhibitor (IC50s 0.143 and 0.076 μM, respectively). SIK2-IN-4 reduces the phosphorylation of transcription coactivator 3 (CRTC3) by targeting SIK1/2, thereby regulating cAMP response element binding protein (CREB)-dependent transcriptional activity. SIK2-IN-4 inhibits the production of pro-inflammatory cytokines such as TNF (IC50: 0.11 µM), IL-12/23 p40 (IC50: 0.25 µM), and IL-23 (IC50: 0.47 µM), while inducing the expression of the anti-inflammatory cytokine IL-10. SIK2-IN-4 can be used to study intestinal inflammation and other chronic inflammatory diseases.
    SIK2-IN-4
  • HY-N1949R
    Homoplantaginin (Standard)
    		Inhibitor
    Homoplantaginin (Standard) is the analytical standard of Homoplantaginin. This product is intended for research and analytical applications. 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 (Standard)
  • HY-B0446R
    Naphazoline hydrochloride (Standard)
    		Inhibitor
    Naphazoline (hydrochloride) (Standard) is the analytical standard of Naphazoline (hydrochloride). This product is intended for research and analytical applications. 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 (Standard)
  • HY-30235
    Benzydamine
    		Inhibitor
    Benzydamine is an orally administered prostaglandin synthesis inhibitor that has anti-inflammatory, analgesic, antipyretic, and antibacterial properties. Benzydamine can inhibit TNF-α, stabilize cell membranes, and reduce oxidative stress within cells.
    Benzydamine
  • HY-P990304
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1)
    		Inhibitor
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1) is a mouse-derived inhibitor that is an IgG2a, κ antibody against mouse 4-1BBL/CD137L.
    Anti-Mouse 4-1BBL/CD137L Antibody (TKS-1)
  • HY-N8593R
    Undecane (Standard)
    		Inhibitor
    Undecane (Standard) is the analytical standard of Undecane. This product is intended for research and analytical applications. Undecane has anti-allergic and anti-inflammatory activities on sensitized rat basophilic leukemia (RBL-2H3) mast cells and HaCaT keratinocytes. In sensitized mast cells, Undecane inhibits degranulation and the secretion of histamine and TNF-α[
    Undecane (Standard)
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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