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-121401
    Myrtenal
    Myrtenal ((±)-Myrtenal) is a monoterpene that acts as an antineoplastic agent. Myrtenal inhibits liver cancer by preventing DEN-PB-induced upregulation of TNF-α protein expression.
    Myrtenal
  • HY-12385
    Ximoprofen
    		Inhibitor
    Ximoprofen is a propionic nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory property. Ximoprofen can be used for ankylosing spondylitis research.
    Ximoprofen
  • HY-N0152R
    Myricitrin (Standard)
    		Inhibitor
    Myricitrin (Standard) is the analytical standard of Myricitrin. This product is intended for research and analytical applications. 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 (Standard)
  • HY-P11001
    RANK-derived TRAF6 inhibitor
    		Inhibitor
    RANK-derived TRAF6 inhibitor is a TRAF6 inhibitor peptide that blocks the interaction of TRAF6 and LMP1 with an IC50 of 177 nM. RANK-derived TRAF6 inhibitor causes a severe reduction in cell viability in the LMP1-dependent lymphoblastoid cell lines (LCLs).
    RANK-derived TRAF6 inhibitor
  • HY-119866
    β-Alethine
    β-Alethine is a disulfide that can be used as an anti-tumor agent and immune adjuvant.
    β-Alethine
  • HY-172870
    PDE4B-IN-4
    		Inhibitor
    PDE4B-IN-4 (Compound 11E) is a PDE4B (IC50: 2.82 nM) and TNF-α (IC50: 7.20 nM) inhibitor. PDE4B-IN-4 inhibits neutrophilia in a mouse lipopolysaccharide (LPS)-induced sepsis model and exhibits anti-inflammatory activity.
    PDE4B-IN-4
  • HY-P991406
    MK-1248
    		Inhibitor
    MK-1248 is a human IgG4 monoclonal antibody (mAb) targeting TNFSF18. MK-1248 enhances the proliferative response of tumor-infiltrating lymphocytes to anti-CD3 stimulation and promotes the production of anti-tumor-associated regulatory cytokines. MK-1248 can be used in solid tumors research.
    MK-1248
  • HY-144737
    Anti-inflammatory agent 15
    		Inhibitor
    Anti-inflammatory agent 15 (compound 29) is a potent antimycobacterial and anti-inflammatory agent. Anti-inflammatory agent 15 inhibits Mtb H37Rv and M299 growth, with MIC50 (minimum inhibitory concentration 50%) of 2.3 and 7.8 μM, respectively. Anti-inflammatory agent 15 inhibits NO through the suppression of iNOS expression, and also inhibited the production of TNF-α and IL-1β. Anti-inflammatory agent 15 can be used for tuberculosis (TB) research.
    Anti-inflammatory agent 15
  • HY-160180
    Glucocorticoid receptor agonist-4 Ala-Ala-Mal
    		Inhibitor
    Glucocorticoid receptor agonist-4 Ala-Ala-Mal (Compound Preparation 9) is an anti-human TNFα antibody-glucocorticoid receptor agonist (GC) conjugate. Glucocorticoid receptor agonist-4 Ala-Ala-Mal can be used in the study of autoimmune and inflammatory diseases.
    Glucocorticoid receptor agonist-4 Ala-Ala-Mal
  • HY-173404
    VB-85247
    		Inducer
    VB-85247 is a STING agonist. VB-85247 induces upregulation of inflammatory cytokines IFNα/β, TNFα, IL6, and CXCL10, as well as maturation and activation of dendritic cells by activating the STING pathway. VB-85247 can achieve regression of intrabladder tumors and can be used in bladder cancer research.
    VB-85247
  • HY-P991513
    BI-655064
    		Inhibitor
    BI-655064, a humanised anti-CD40 antibody with has fragment crystallisable (Fc) regions with two mutations that prevent Fc-mediated antibody-dependent or complement-mediated cellular cytotoxicity and platelet activation. BI-655064 can be used for the study of autoimmune disease, such as lupus nephritis and rheumatoid arthritis (RA).
    BI-655064
  • HY-P990280
    Anti-Mouse CD27 Antibody (RM27-3E5)
    		Inhibitor
    Anti-Mouse CD27 Antibody (RM27-3E5) is an agonistic rat-derived IgG2a κ type antibody, targeting to mouse CD27. Anti-Mouse CD27 Antibody (RM27-3E5) stimulates CD 27. Anti-Mouse CD27 Antibody (RM27-3E5) can be used for the researches of cancer and immunology, such as B16cOVA tumor.
    Anti-Mouse CD27 Antibody (RM27-3E5)
  • HY-B0809S1
    Theophylline-d3
    		Inhibitor
    Theophylline-d3 is deuterated labeled Theophylline (HY-B0809). Theophylline (1,3-Dimethylxanthine) is a potent phosphodiesterase (PDE) inhibitor, adenosine receptor antagonist, and histone deacetylase (HDAC) activator. Theophylline (1,3-Dimethylxanthine) inhibits PDE3 activity to relax airway smooth muscle. Theophylline (1,3-Dimethylxanthine) has anti-inflammatory activity by increase IL-10 and inhibit NF-κB into the nucleus. Theophylline (1,3-Dimethylxanthine) induces apoptosis. Theophylline (1,3-Dimethylxanthine) can be used for asthma and chronic obstructive pulmonary disease (COPD) research.
    Theophylline-d<sub>3</sub>
  • HY-159144
    Anti-inflammatory agent 91
    		Inhibitor
    Anti-inflammatory agent 91 (Compound 4o) is an anti-inflammatory agent that can reduce inflammatory cytokines by inhibiting the STAT3 and NF-κB signaling pathways. Anti-inflammatory agent 91 can be used in research to improve skin inflammation associated with psoriasis.
    Anti-inflammatory agent 91
  • HY-111167
    AN-2898
    		Inhibitor
    AN-2898 is a selective PDE4 inhibitor with IC50 of 0.027 μM over other phosphodiesterase enzymes, such as PDE1A, PDE2A and PDE3A. AN-2898 also potently inhibits PDE4 subtypes (PDE4B1, PDE4A1A and PDE4D2). AN-2898 significantly inhibits the production of TNF-α, IL-2, IFN-γ, IL-5 and IL-10. AN-2898 can be used for mild to moderate atopic dermatitis (AD) and psoriasis research.
    AN-2898
  • HY-149331
    TNF-α-IN-11
    		Inhibitor
    TNF-α-IN-11 (Compound 10) is a TNF-α inhibitor with a KD value of 12.06 μM. TNF-α-IN-11 binds to TNF-α and blocks the activation of TNF-α-trigged caspase and NF-κB signaling pathway. TNF-α-IN-11 inhibits the phosphorylation of IκBα, as well as the nuclear translocation of NF κB p65. TNF-α-IN-11 can be used for research of TNF-α-mediated autoimmune diseases.
    TNF-α-IN-11
  • HY-124954
    MN-25
    MN-25 (compound 4a) is an orally active indolpyridone that serves as a novel cannabinoid ligand. MN-25 has Ki of 245 nM and 11 nM for CB1 and CB2. MN-25 has CB2 agonist activity and inhibits TNF-R release in human peripheral blood mononuclear cells in vitro with an IC50 of 33 μM. MN-25 shows efficacy in a mouse acute inflammation model at oral doses up to 50 mg/kg>[1].
    MN-25
  • HY-175813
    NPSR1 antagonist-1
    		Inhibitor
    NPSR1 antagonist-1 is a potent and peripherally restricted neuropeptide S receptor 1 (NPSR1) antagonist. NPSR1 antagonist-1 can inhibit IL-6, PTGS2, IL-20, and CXCL8 expression. NPSR1 antagonist-1 can reduce TNF-α cytokine levels. NPSR1 antagonist-1 can be used for the research of inflammation, such as peritonitis.
    NPSR1 antagonist-1
  • HY-162797
    PDE4-IN-18
    		Inhibitor
    PDE4-IN-18 (compound 1l) is a PDE4 inhibitor (IC50=1.55 μM) with anti-inflammatory activity. PDE4-IN-18 exerts anti-inflammatory effects by reducing excessive immune cell infiltration and intestinal membrane formation, as well as reducing the mRNA expression of pro-inflammatory cytokines (such as TNF-α and IL-6) in synovial tissue. PDE4-IN-18 can be used in the study of rheumatoid arthritis and psoriasis.
    PDE4-IN-18
  • HY-P990809
    Anti-Mouse 4-1BB/CD137 Antibody (LOB12.3)
    Anti-Mouse 4-1BB/CD137 Antibody (LOB12.3) is an agonistic rat-derived IgG1 κ type antibody, targeting to mouse 4-1BB/CD137. Anti-Mouse 4-1BB/CD137 Antibody (LOB12.3) can stimulate 4-1BB signaling and induce T cell mediated antitumor immunity. Anti-Mouse 4-1BB/CD137 Antibody (LOB12.3) can be used for the researches of cancer, infection, immunology and neurological disease, such as glioblastoma and retrovirus infection.
    Anti-Mouse 4-1BB/CD137 Antibody (LOB12.3)
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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