2. Signalwege
  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
Art. -Nr. Produktname Wirkung Reinheit Chemical Structure
  • HY-16362
    Omtriptolide sodium
    		Inhibitor
    Omtriptolide sodium (PG490-88Na) is a derivative of Triptolide (HY-32735). Omtriptolide sodium exhibits significant immunosuppressive, anti-fibrotic and anti-inflammatory properties. The mechanism of action of Omtriptolide sodium is diverse, including inhibiting T cell activation and proliferation, inducing T cell apoptosis (apoptosis), blocking fibroblast maturation/proliferation, inhibiting TGF-β mRNA expression, and suppressing pro-inflammatory cytokines (such as IL-2, IFN-γ, TNF-α) by blocking transcription factors such as NF-κB. Omtriptolide sodium can be used for research on obstructive airway diseases, pulmonary fibrosis and graft-versus-host disease.
    Omtriptolide sodium
  • HY-182469
    FuBIG
    		Inhibitor
    FuBIG is an iminoguanidine derivative with neuroprotective effects. FuBIGL inhibits L-LDH activation and reduces lactate production. FuBIGL exerts protective effects on inflammatory nerve cells, upregulates the expressions of AMPK, pAMPK and FOXO3, and activates the AMPK pathway in cells. FuBIG exerts anti-inflammatory effects by reducing pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and increasing the anti-inflammatory cytokine IL-10. FuBIG maintains mitochondrial membrane potential, alleviates mitochondrial dysfunction, reduces ROS production, and relieves oxidative stress. FuBIG upregulates Bcl-2, downregulates Bax and Caspase-3, and inhibits cell apoptosis (apoptosis). FuBIG improves metabolic disorders in diabetic mice, decreases the levels of LDL-C, ALT and AST, and increases HDL-C level simultaneously. FuBIG can be used in the research of diabetic neuroinflammation.
    FuBIG
  • HY-N5054
    (R)-5,7-Dimethoxyflavanone
    		Inhibitor 99.98%
    (R)-5,7-Dimethoxyflavanone shows potent antimutagenic activity against MeIQ mutagenesis in Ames test using the S. typhimurium TA100 and TA98 strains. And (R)-5,7-Dimethoxyflavanone significantly and dose-dependently inhibits the inflammatory mediato.
    (R)-5,7-Dimethoxyflavanone
  • HY-178497
    ZJK-807
    		Inhibitor
    ZJK-807 is a highly effective and selective PROTAC degrader targeting KRASG12D (DC50 = 79.5 nM in AsPC-1 cells). ZJK-807 shows minimal impact on wild-type KRAS or other mutants (G12C/S/V, G13D), inducing mutant-specific cytotoxicity. ZJK-807 suppresses RAS/MAPK signaling and uniquely modulates TNF signaling and eukaryotic ribosome biogenesis. ZJK-807 can be used for the study of KRAS-driven pancreatic cancer. Yellow: KRASG12D ligand (HY-W087383); Green: E3 ligase CRBN ligand (HY-178507); Black: Linker (HY-178506).
    ZJK-807
  • HY-178012
    GLPG4471
    		Inhibitor
    GLPG4471 is a selective and orally active IRAK4 inhibitor with an IC50 of 1.7 nM. GLPG4471 exhibits potent inhibition of cytokine (TNFα and IFNα) secretion in cellular and whole blood phenotypic assays. GLPG4471 displays significant activity in a mouse model of collagen-induced arthritis. GLPG4471 can be used for the study of arthritis.
    GLPG4471
  • HY-P11242
    Cm-CATH2
    		Inhibitor
    Cm-CATH2 is an antimicrobial peptide discovered from Chelonia mydas. Cm-CATH2 has a potent, broad-spectrum and rapid bactericidal ability by rapidly destroying the integrity of bacterial cell membranes. It shows strong activity against Gram-positive bacteria (such as VREF, Staphylococcus aureus), Gram-negative bacteria (such as Escherichia coli, Klebsiella pneumoniae), and fungi (such as Candida albicans) with MICs ranges from 1.17 to 18.75 μg/mL. Cm-CATH2 is also effective against various aquatic pathogenic bacteria. Cm-CATH2 not only inhibits biofilm formation but can also remove the formed biofilms. Cm-CATH2 has immunomodulatory functions and chemotactic effects on immune cells, and can inhibit the production of pro-inflammatory cytokines by macrophages stimulated by LPS (HY-D1056). Cm-CATH2 prevents the activation of NF-κB by inhibiting the degradation of IκBα, and also inhibits the phosphorylation of MAPK signaling pathways (p38, JNK, ERK). Cm-CATH2 demonstrates strong anti-infective ability in mouse peritonitis models and pneumonia models.
    Cm-CATH2
  • HY-P991823
    Anti-Mouse CD120a Antibody (55R-593)
    		Inhibitor
    Anti-Mouse CD120a Antibody (55R-593) reacts with the mouse CD120a. CD120a is expressed independently of TNFRII at low levels on a wide variety of cell types. Recommend Isotype Controls: Polyclonal Armenian hamster IgG, Isotype Control (HY-P990305).
    Anti-Mouse CD120a Antibody (55R-593)
  • HY-179646
    CIAC101
    		Inhibitor
    CIAC101 is a potent and brain-penetrant TLR4 antagonist with an IC50 of 17.0 nM in NO assay. CIAC101 blocks Lipopolysaccharides (HY-D1056) (LPS)-induced NF-κB activation and reduces the expression of pro-inflammatory mediators (iNOS, IL-1β, TNF-α, and IL-6). CIAC101 robust antineuroinflammatory activity with efficacy against drug-evoked neurobehavioral adaptations. CIAC101 can be used for the research of addiction and neurological disease.
    CIAC101
  • HY-P991405
    EU-102
    		Inhibitor
    EU-102 is a human monoclonal antibody (mAb) targeting TNFSF18. EU-102 can be used in solid tumors research.
    EU-102
  • HY-138623
    GSK789
    		Inhibitor
    GSK789 is a selective inhibitor of BET BD1. GSK789 inhibits the growth of leukemia cell lines. GSK789 inhibits LPS-stimulated production of MCP-1, TNFα and IL-6 in human whole blood. GSK789 exhibits antiproliferative, anti-inflammatory and immunomodulatory activities. GSK789 can be used in research related to cancers such as leukemia, as well as inflammatory and immune diseases.
    GSK789
  • HY-14869
    Revamilast
    		Inhibitor
    Revamilast (GRC 4039) is an orally active phosphodiesterase-4 (PDE4) inhibitor with an IC50 of 3 nM. Revamilast inhibits the production of TNF-α. It can be used for research on rheumatoid arthritis, plaque psoriasis, asthma, and other inflammatory diseases.
    Revamilast
  • HY-180109
    Benzo-17R-RvD2
    		Inhibitor
    Benzo-17R-RvD2 (Benzo-17R-Resolvin D2) is a benzo-containing analog of RvD2 (HY-121636). Benzo-17R-RvD2 enhances human macrophage efferocytosis, limits neutrophil infiltration, reduces TNF-α, and increases IL-1 receptor antagonist in peritonitis. Benzo-17R-RvD2 promotes E. coli killing by human leukocytes and reduces neutrophil swarm area without compromising anti-Candida activity. Benzo-17R-RvD2 activates the human-RvD2 receptor with an EC50 ∼1.5 nM. Benzo-17R-RvD2 can be used in research on inflammation-associated diseases such as cardiovascular disease, cancer, neuroinflammation, pain, and muscle regeneration.
    Benzo-17R-RvD2
  • HY-N0182S3
    Fisetin-d5
    		Inhibitor
    Fisetin-d5 is a deuterated labeled Fisetin. Fisetin is a natural flavonol found in many fruits and vegetables with various benefits, such as antioxidant, anticancer, neuroprotection effects.
    Fisetin-d<sub>5</sub>
  • HY-178166
    ETI41
    		Inhibitor
    ETI41 is an orally active, selective TLR inhibitor that targets the nucleoside-binding Site I on TLR7 (IC50 = 0.63 μM) and TLR9 (IC50 = 0.16 μM), sparing surface TLRs (including TLR1/TLR2, TLR2/TLR6, TLR4 and TLR5). ETI41 potently inhibits endosomal TLR-mediated pro-inflammatory signaling with nanomolar activity in cellular, biophysical and in vivo assays. ETI41 suppresses the expression of inflammation-associated genes and effectively ameliorates symptoms in mouse models of psoriasis, and systemic lupus erythematosus (SLE). ETI41 can be used for autoimmune and inflammatory diseases research.
    ETI41
  • HY-174825
    TRPM8 antagonist 4
    		Inhibitor
    TRPM8 antagonist 4 is a CB2R partial agonist (EC50=54.2 nM, Ki=3.2 μM) and TRPM8 antagonists (IC50=42.3 nM) with high functional selectivity and good physicochemical properties. TRPM8 antagonist 4 has significant anti-inflammatory and analgesic effects and good safety, reduces the mRNA expression of TNF-α, IL-6, and IL-1β.
    TRPM8 antagonist 4
  • HY-182707
    JWX-A0108
    		Inhibitor
    JWX-A0108 is a selective human α7 nAChR positive allosteric modulator with an EC50 of 4.35 μM. JWX-A0108 potentiates α7 nAChR currents only in the presence of acetylcholine, with no direct activating effect or alteration of desensitization. JWX-A0108 enhances hippocampal GABAergic synaptic transmission by increasing spontaneous inhibitory postsynaptic currents. JWX-A0108 reduces the brain expression levels of IL-1β, TNF-α, and IL-6 by blocking the NF-κB signaling pathway, and reduces microglial activation by downregulating Iba1. JWX-A0108 effectively improves cognitive deficits, neuroinflammation, and hippocampal neuronal damage in mouse models of schizophrenia and Alzheimer's disease. JWX-A0108 can be used for research related to schizophrenia and Alzheimer's disease.
    JWX-A0108
  • HY-114980
    BMS-279700
    		Inhibitor
    BMS-279700 is an orally active Src-family kinase p56Lck inhibitor. BMS-279700 can block the production of proinflammatory cytokines (IL-2 and TNFα). BMS-279700 can inhibit T cell proliferation. BMS-279700 can be used for the researches of inflammation and immunology.
    BMS-279700
  • HY-161833
    HSP90-IN-31
    		Inhibitor
    HSP90-IN-31 (compound Be01) causes reduction of CD80 and CD86 expression on dendritic cells (DCs). HSP90-IN-31 decreases the production of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in BMDC and peritoneal macrophages stimulated by LPS (HY-D1056). Under the delayed-type hypersensitivity (DTH) mice model, HSP90-IN-31 reduces ear swelling and pro-inflammatory cytokines in the spleen.
    HSP90-IN-31
  • HY-N0042R
    Ginsenoside Rc (Standard)
    		Inhibitor
    Ginsenoside Rc (Standard) is the analytical standard of Ginsenoside Rc. This product is intended for research and analytical applications. Ginsenoside Rc, one of major Ginsenosides from Panax ginseng, enhances GABA receptorA (GABAA)-mediated ion channel currents (IGABA). Ginsenoside Rc inhibits the expression of TNF-α and IL-1β.
    Ginsenoside Rc (Standard)
  • HY-P99543
    Tulinercept
    		Inhibitor
    Tulinercept (OPRX-106) is a recombinant TNF receptor fusion protein fused to an IgG1 Fc domain.
    Tulinercept
Art. -Nr. Produktname / Synonyms Species Source
Art. -Nr. Produktname / 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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