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-W115786
    Kaolin
    		Activator
    Kaolin is a family of kaolinitic clays, which is found in the earth's crust. Kaolin alleviates the toxicity of graphene oxide for mammalian cells. Kaolin can be utilized in industrial, cosmetic and medical fields, excipient.
    Kaolin
  • 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-B0898
    Ceftiofur sodium
    		Inhibitor 98.03%
    Ceftiofur sodium is a cell wall synthesis inhibitor that targets bacterial penicillin-binding proteins (PBPs) and has anti-inflammatory effects in endotoxemia. Ceftiofur sodium exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycan, leading to bacterial cell lysis. Ceftiofur sodium 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 sodium
  • HY-P991192
    BI-1808
    		Inhibitor
    BI-1808 is a human IgG1 monoclonal antibody that targets TNFR2by blocking interaction of TNFR2 with ligand TNF-α, confers FcγR-dependent depletion of Treg and mediates expansion of intratumoral CD8+ T cells.
    BI-1808
  • HY-P99940
    Remtolumab
    		Inhibitor 99.24%
    Remtolumab (ABT-122) is a dual-variable domain immunoglobulin that neutralises both tumor necrosis factor α (TNFα) and IL-17A. Remtolumab shows dual inhibition of TNFα and IL-17A. Remtolumab can be used for rheumatoid arthritis (RA) research.
    Remtolumab
  • HY-100176
    PF-4878691
    		99.89%
    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
  • 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-169118
    EGR-1-IN-2
    		Inhibitor 99.61%
    EGR-1-IN-2 (compound 2) is an EGR-1 inhibitor with anti-inflammatory activity. EGR-1-IN-2 inhibits the formation of EGR-1-DNA complexes induced by TNF-α in HaCaT cells.
    EGR-1-IN-2
  • HY-P990242
    Anti-Mouse Galectin-9 Antibody (RG9-1)
    		Inhibitor
    Anti-Mouse Galectin-9 Antibody (RG9-1) is an anti-mouse Galectin-9 IgG2b monoclonal antibody. Anti-Mouse Galectin-9 Antibody (RG9-1) promotes inflammatory response by enhancing the secretion of IFN-γ, TNF-α, and IL-6. Anti-Mouse Galectin-9 Antibody (RG9-1) can increase CD8 T cell and Treg frequency. Anti-Mouse Galectin-9 Antibody (RG9-1) reduces graft survival time by increasing CD4+ and CD8+ T cell infiltration. Anti-Mouse Galectin-9 Antibody (RG9-1) can be used for researches on inflammation conditions, cancer and xenotransplantation such as ischemia-reperfusion, colon cancer, breast cancer and leukemia.
    Anti-Mouse Galectin-9 Antibody (RG9-1)
  • HY-W099602
    Dodecane
    		Activator 99.58%
    Dodecane (Ba 51-090453) is an ester product. Dodecane is an aliphatic hydrocarbon. Dodecane can result in a high TNF-α expression and transepidermal waterloss (TEWL).
    Dodecane
  • 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
  • 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-Y1322
    Triphenyl phosphate
    		Activator 99.67%
    Triphenyl phosphate is an organic phosphate flame retardant. Triphenyl phosphate can disrupt placental tryptophan metabolism by activating MAOA/ROS/NFκB, leading to abnormal neurological behavior. Triphenyl phosphate promotes oxidative stress by inducing inflammatory factors like nuclear factor kappa B (NFκB), interleukin-6, and tumor necrosis factor α. Triphenyl phosphate can also cause allergic contact dermatitis.
    Triphenyl phosphate
  • HY-123885
    NSC243928 mesylate
    		99.33%
    NSC243928 mesylate is a human lymphocyte antigen 6 (LY6) binder, which also acts as an inhibitor of cell growth and has anticancer activity.
    NSC243928 mesylate
  • HY-N0358
    1,4-Dicaffeoylquinic acid
    		Inhibitor 98.44%
    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-126066
    (-)-Syringaresinol
    		Inhibitor 99.95%
    (-)-Syringaresinol is an orally active isomer of syringaresinol (HY-N8307) found in Annona Montana. (-)-Syringaresinol exhibits antioxidant, anti-inflammatory, and anticancer activities. (-)-Syringaresinol can alleviate ulcerative colitis via the PI3K-Akt/MAPK/Wnt signaling pathway. (-)-Syringaresinol inhibits HL-60 cell proliferation by arresting the G1 phase and inducing apoptosis. (-)-Syringaresinol inhibits LPS (HY-D1056)-induced microglial activation by downregulating the NF-κB p65 signaling pathway and its interaction with ERβ, exerting anti-neuroinflammatory effects.
    (-)-Syringaresinol
  • HY-N6255
    Ilexgenin A
    		98.33%
    Ilexgenin A is a pentacyclic triterpenoid, which extracted from Ilex hainanensis Merr. Ilexgenin A can be used for the research of inflammation and cancer.
    Ilexgenin A
  • HY-P990111
    BMS-986325 (anti-CD40)
    		Inhibitor
    BMS-986325 (anti-CD40) is a CD40 inhibitor, and can be used for primary Sj gren's syndrome research.
    BMS-986325 (anti-CD40)
  • HY-P1825A
    TNF-α (10-36), human TFA
    TNF-α (10-36), human (TFA) is a peptide of human TNF-α.
    TNF-α (10-36), human TFA
  • HY-124339
    JNJ525
    		Inhibitor 99.93%
    JNJ525 (compound 1) is a TNFα inhibitor with the IC50 values of 1.2 μM and 1.1 μM against of TNFR1 and TNFR2, respectively.
    JNJ525
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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