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-125740R
    Malvidin-3-glucoside chloride (Standard)
    		Inhibitor
    Malvidin-3-glucoside (Malvidin-3-O-glucoside; Oenin) chloride (Standard) is the analytical standard of Malvidin-3-glucoside chloride (HY-125740). This product is intended for research and analytical applications. Malvidin-3-glucoside chloride is an orally active inhibitor of the NF-κB pathway, which blocks inflammatory responses induced by TNF-α, reduces IκB-α degradation and p65 nuclear translocation, and upregulates endothelial nitric oxide synthase eNOS to increase NO production. Malvidin-3-glucoside chloride exerts anti-inflammatory and antioxidant effects by inhibiting pro-inflammatory molecules such as MCP-1, ICAM-1, and IL-6, and regulating intestinal microorganisms and metabolites, while protecting endothelial cells and improving intestinal microecological dysbiosis under inflammatory conditions. Malvidin-3-glucoside chloride can be used to study chronic inflammatory-related diseases such as atherosclerosis and inflammatory bowel disease, and has the potential to prevent vascular inflammation and improve intestinal health.
    Malvidin-3-glucoside chloride (Standard)
  • HY-N9867
    Gnetifolin E
    		Inhibitor
    Gnetifolin E is a resveratrol trimer derivative that can be isolated from Gnetum brunonianum. Gnetifolin E has anti-inflammatory activity, and inhibits TNF-α.
    Gnetifolin E
  • HY-Y0399S
    L-Norvaline-d5
    		Antagonist
    L-Norvaline-d5 is the deuterium labeled L-Norvaline. L-Norvaline is the inhibitor for arginase, that promotes the production of NO, reduces oxidative stress, improves insulin resistance, and exhibits antioxidant and anti-hyperglycemic effects. L-Norvaline can be used in research of Alzheimer’s disease.
    L-Norvaline-d<sub>5</sub>
  • HY-114592
    M199
    		Activator 98.55%
    M199 is a potent TLR3/TLR9 signaling inhibitor. M199 induces secretion of IL-6, IL-8 and TNFα in human PBMCs. M199 is used as a selective inducer of the immune response.
    M199
  • HY-P991401
    GSK2862277
    		Antagonist
    GSK2862277 is a human monoclonal antibody (mAb) targeting TNFRSF1A. GSK2862277 increases neutrophil extracellular trap formation and alveolar macrophage phagocytosis. GSK2862277 can be used in Acute lung injury and Acute Respiratory Distress Syndrome (ARDS) research. Recommended isotype control: VHH-hFc.
    GSK2862277
  • HY-153329
    TNF-α-IN-9
    		Inhibitor
    TNF-α-IN-9 (compound 48) is a analog of NDM-1 inhibitor-3 (HY-150758). TNF-α-IN-9 is a TNF-α inhibitor. TNF-α-IN-9 shows low inhibitory activity.
    TNF-α-IN-9
  • HY-153952
    Immuno modulator-1
    		Inhibitor
    Immuno modulator-1 (compound 22) inhibits TNFα and IL-2 secretion in human peripheral blood mononuclear cells (hPBMC), with IC50 values of 4.7 and 26 nM, respectively. Immuno modulator-1 shows hERG potassium channel blocking effect, with Inhibitory percentage of 20% at 3 μM.
    Immuno modulator-1
  • HY-161821
    Antitumor agent-173
    		Control
    Antitumor agent-173 (Compound 4b) is a prodrug of Cycloicaritin (HY-N1940). Antitumor agent-173 is a substrate for OATP2B1. Antitumor agent-173 selectively inhibits the growth of tumor Antitumor agent-173 significantly increases the oral bioavailability of Cycloicaritin and exerts good antitumor activity and safety.
    Antitumor agent-173
  • HY-P991070
    ADG-106
    		Agonist
    ADG-106 is a fully human agonistic monoclonal IgG4 antibody against CD137 (4-1BB). ADG-106 has the mechanism to activate CD137 via strong FcγRIIB-mediated crosslinking while antagonizing CD137 ligands. The isotype control for ADG-106 can refer to Human IgG4 (S228P) kappa, Isotype Control (HY-P99003).
    ADG-106
  • HY-N0822R
    Shikonin (Standard)
    		Inhibitor
    Shikonin (Standard) is the analytical standard of Shikonin. This product is intended for research and analytical applications. Shikonin is a major component of a Chinese herbal medicine named zicao. Shikonin is a potent TMEM16A chloride channel inhibitor with an IC50 of 6.5 μM. Shikonin is a specific pyruvate kinase M2 (PKM2) inhibitor and can also inhibit TNF-α and NF-κB pathway. Shikonin decreases exosome secretion through the inhibition of glycolysis. Shikonin inhibits AIM2 inflammasome activation.
    Shikonin (Standard)
  • HY-P991403
    BC011
    		Inhibitor
    BC011 is a human monoclonal antibody (mAb) targeting TNFRSF1B. BC011 promotes CD8+T cell proliferation and depletes Treg cells, thereby increasing the proportion of effector T cells in the tumor microenvironment. BC011 can be used in tumor Immunity research.
    BC011
  • HY-172590
    LZ-07
    		Inhibitor
    LZ-07 is a IRAK4 PROTAC degrader (DC50 = 1.14 nM). LZ-07 leads to marked suppression of cytokines including IL-6, IL-1β, TNF-α, and IL-10 upon degradation of IRAK4. LZ-07 can be studied in research for autoimmune diseases (Pink: IRAK4 ligand (HY-172591); Blue: CRBN ligand (HY-34590); Black: linker (HY-B0149); CRBN ligand + linker: HY-172593).
    LZ-07
  • HY-128754R
    Monoolein (Standard)
    		Inhibitor
    Monoolein is a biocompatible lipid molecule that can be used as a carrier for bone repair. Monoolein exhibits anti-inflammatory activity by inhibiting the immune response induced by LPS (HY-D1056). It exerts its anti-inflammatory effects by reducing the production of immune response factors such as IL-12 p40, IL-6, and TNF-α, and inhibiting the generation of NO. Monoolein can be used in drug delivery and research in the field of inflammatory diseases .
    Monoolein (Standard)
  • HY-N10454
    Sinulatumolin C
    		Inhibitor
    Sinulatumolin C (compound 3) is an anti-inflammatory agent. Sinulatumolin C has significant TNF-α inhibitory activity with an IC50 value of 2.6 μM.
    Sinulatumolin C
  • HY-163162
    Anhydro-Ouabain
    		Inhibitor
    Anhydro-Ouabain (compound 20) is a cardiotonic steroid which shows anti-inflammatory and neuroprotective activities and thus can be used in neurological research.
    Anhydro-Ouabain
  • HY-W015490S
    1,4-Naphthoquinone-d6
    		Inhibitor
    1,4-Naphthoquinone-d6 is the deuterium labeled 1,4-Naphthoquinone. 1,4-Naphthoquinone is an inhibitor with broad-spectrum inhibitory activity targeting DNA polymerase, NF-κB and monoamine oxidase (MAO-A/B), with antibacterial and anti-biofilm efficacy. 1,4-Naphthoquinone is a competitive inhibitor of MAO-B (Ki=1.4 μM) and a non-competitive inhibitor of MAO-A (Ki=7.7 μM). 1,4-Naphthoquinone inhibits DNA polymerase pol α, β, γ, δ, ε, λ with IC50 ranging from 5.57-128 μM. 1,4-Naphthoquinone inhibits tumor cell proliferation, induces apoptosis and necrosis, and has anti-angiogenic and anti-inflammatory activities by inducing oxidative stress, depleting glutathione (GSH), inhibiting DNA polymerase-mediated DNA synthesis and blocking NF-κB nuclear translocation. 1,4-Naphthoquinone can be used in anti-bacterial , anti-tumor and anti-inflammatory studies, including inhibition of melanoma and colon cancer cell growth and endothelial cell function, as well as LPS-induced inflammation models.
    1,4-Naphthoquinone-d<sub>6</sub>
  • HY-115577
    Mitochonic acid 35
    		Inhibitor
    Mitochonic acid 35 is an IAA analogue with cytoprotective effects.
    Mitochonic acid 35
  • HY-171592
    RIPK2-IN-7
    		Inhibitor
    RIPK2-IN-7 (Compound 10w) is an orally active, selective RIPK2 inhibitor (IC50: 0.6 nM). RIPK2-IN-7 inhibits RIPK2 kinase activity, blocks the nucleotide-binding oligomerization domain (NOD) signaling pathway, and reduces the production of inflammatory factors (such as TNFα). RIPK2-IN-7 can be used in the study of inflammatory bowel disease (IBD).
    RIPK2-IN-7
  • HY-P991195
    SIM-0235
    		Inhibitor
    SIM-0235 is humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets and inhibits TNFR2, the recommed isotype control is Human IgG1 kappa, Isotype Control (HY-P99001)[1].
    SIM-0235
  • HY-N7699A
    D-Trimannuronic acid
    		Activator
    D-Trimannuronic acid, an alginate oligomer is extracted from seaweed. D-Trimannuronic acid can induce TNF‐α secretion by mouse macrophage cell lines. D-Trimannuronic acid can be used for the research of pain and vascular dementia.
    D-Trimannuronic acid
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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