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-N0616
    Trifolirhizin
    		98.37%
    Trifolirhizin is a pterocarpan flavonoid isolated from the roots of Sophora flavescens. Trifolirhizin possesses potent tyrosinase inhibitory activity with an IC50 of 506 μM. Trifolirhizin exhibits potential anti-inflammatory and anticancer activities.
    Trifolirhizin
  • HY-P5645
    LEAP-2
    		Activator
    LEAP-2 (Human liver expressed antimicrobial peptide-2) is a GHS-R1a antagonist, with an IC50 of 6.0 nM. LEAP-2 suppresses the orexigenic effect of ghrelin. LEAP-2 attenuates ghrelin-induced growth hormone (GH) release and reduces basal food intake. LEAP-2 exhibits antimicrobial activity against microbial model organisms. LEAP-2 can be used for the study of obesity and infection.
    LEAP-2
  • HY-101448
    TMI-1
    		Inhibitor 99.57%
    TMI-1 (WAY-171318) inhibits TNF converting enzyme (TACE) (IC50 of 8.4 nM), ADAM-TS-4, ADAM-17 and various MMPs with oral activity. TMI-1 significantly suppresses the secretion of TNF-α , alleviating collagen-induced arthritis in mice. TMI-1 inhibits cancer cell proliferation, induces apoptosis through a caspase-dependent pathway. TMI-1 also reverses TRPV1 upregulation and lowers the levels of inflammatory factors (TNF-α、IL-1β、IL-6) in nerve cells, protecting against paclitaxel-induced neurotoxicity. TMI-1 leads to changes in pro-atherogenic lipoprotein profiles, but does not affect the progression of early lesions.
    TMI-1
  • HY-P99934
    Eftozanermin alfa
    		Inhibitor
    Eftozanermin alfa (ABBV-621) is a tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist. Eftozanermin alfa is a fusion protein consisting of a mutant immunoglobulin G1-Fc linked to 2 single-chain trimers of TRAIL. Eftozanermin alfa induces apoptosis in tumor cells by activation of death receptors (DR4 receptor and DR5 receptor) with Kds of 780 nM and 635 nM. Eftozanermin alfa can be used for the research of multiple solid and heme malignancies.
    Eftozanermin alfa
  • HY-W082785A
    L6H21
    		Inhibitor 99.19%
    L6H21, a Chalcone (HY-121054) derivative, is an orally active, potent and specific myeloid differentiation 2 (MD-2) inhibitor. L6H21 directly binds to MD-2 protein with a high affinity and low KD value of 33.3 μM, blocking the formation of the LPS-TLR4/MD-2 complex. L6H21 inhibits LPS-induced expression of TNF-α and IL-6 in RAW264.7 macrophages, with IC50 values of 6.58 and 8.59 μM, respectively. L6H21 can be used for alcoholic liver disease, metabolic disturbance and neuroinflammation research.
    L6H21
  • HY-P99057
    Varlilumab
    		Inhibitor
    Varlilumab (CDX-1127) is an agonist anti-CD27 monoclonal antibody. Varlilumab can promote T cell expansion and activate the immune response. Varlilumab has anti-tumor activity and can be used in the research of hematological malignancies and solid tumors.
    Varlilumab
  • HY-N1887
    4-Allylcatechol
    		Inhibitor 98.60%
    4-Allylcatechol (4-Allylpyrocatechol) is a xylan which has oral activity and can be isolated from the root of Piper taiwanense. 4-Allylcatechol has a strong inhibitory activity against collagen-induced platelet aggregation (IC50 = 5.3 μM). In addition, 4-Allylcatechol has anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv (MIC = 27.6 μg/mL).
    4-Allylcatechol
  • HY-119307
    Apratastat
    		Inhibitor 99.28%
    Apratastat (TMI-005) is an orally active, non-selective and reversible TACE/MMPs inhibitor, can inhibit inhibit the release of TNF-α. Apratastat has the potential to overcome radiotherapy-resistance in non-small cell lung cancer (NSCLC). Apratastat is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
    Apratastat
  • HY-110036
    GW-405833
    		Inhibitor 98.91%
    GW-405833 (L768242) is a potent, selective cannabinoid receptor 2 (CB2) agonist. GW405833 has EC50 and Ki values ​​of 0.65 nM and 3.92 nM for CB2, and EC50 and Ki values ​​of 16.1 μM and 4772 nM for CB1. GW-405833 also exhibits non-competitive CB1 antagonist, exerting its analgesic and and anti-inflammatory effect through a CB1 receptor (rather than CB2) dependent mechanism. GW-405833 can significantly inhibit the production of cAMP stimulated by Forskolin (HY-15371). GW405833 inhibits glycolysis by down-regulating HIF-1α, thereby alleviating acute liver failure (ALF).
    GW-405833
  • HY-W015490
    1,4-Naphthoquinone
    		Inhibitor 99.97%
    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
  • HY-N2055
    Kaempferol 3-O-sophoroside
    		Inhibitor 99.41%
    Kaempferol 3-O-sophoroside is an orally active derivative of Kaempferol. It exhibits anti-inflammatory, analgesic, and antidepressant effects. Kaempferol 3-O-sophoroside is an inhibitor of the cell surface receptor toll-like receptor (TLR) 2/4 for High mobility group box 1 (HMGB1), and it also exerts anti-inflammatory effects by blocking the activation of NF-κB expression and the production of TNF-α. Kaempferol 3-O-sophoroside promotes the production of brain-derived neurotrophic factor (BDNF) and enhances autophagy by binding to AMP-activated protein kinase (AMPK), thereby exerting antidepressant effects. Kaempferol 3-O-sophoroside holds promise for research in the fields of inflammation and neurodegenerative diseases.
    Kaempferol 3-O-sophoroside
  • HY-N2086
    Ethyl palmitate
    		Inhibitor 99.09%
    Ethyl palmitate (Ethyl hexadecanoate) is a CHIKV virus inhibitor with an EC50 value of 0.0068 μM. Ethyl palmitate can reduce levels of TNF-α, IL-6, and NF-κB in endotoxemic rats, showing anti-inflammatory activity.
    Ethyl palmitate
  • HY-76938
    Actarit
    		Inhibitor 99.58%
    Actarit (4-Acetylaminophenylacetic acid) is an orally active Carbonic Anhydrase II (CAII) inhibitor with an IC50 of 422 nM. Actarit shows suppressive effects experimental autoimmune encephalomyelitis in rats. Actarit inhibits the development of type ll collagen (CII)-induced arthritis in mice by suppressing delayed-type hypersensitivity to CII. Actarit can be used for the study of Multiple Sclerosis (MS) and rheumatoid arthritis.
    Actarit
  • HY-P990680
    Anti-Mouse CD40 Antibody (FGK4.5/FGK45)
    		Inhibitor
    Anti-Mouse CD40 Antibody (FGK4.5/FGK45) is an agonistic rat-derived IgG2a monoclonal antibody targeting mouse CD40. Anti-Mouse CD40 Antibody (FGK4.5/FGK45) enhances T cells responses, dendritic cells maturation and NK cells activation. Anti-Mouse CD40 Antibody (FGK4.5/FGK45) can be used for the researches of cancer, infection, inflammation and immunology, such as CT26 tumor, vesicular stomatitis virus (VSV) infection and transplantation.
    Anti-Mouse CD40 Antibody (FGK4.5/FGK45)
  • HY-P99325
    Toralizumab
    		Inhibitor 99.57%
    Toralizumab (IDEC-131) is a humanized monoclonal antibody (mAb) against CD40L (CD154) comprised of human gamma 1 heavy chains and human kappa light chains. Toralizumab binds specifically to human CD40L on T cells, thereby preventing CD40 signaling. Toralizumab is an immunosuppressive agent. Toralizumab can lead to increased thrombosis. Toralizumab can be studied in research for diseases such as multiple sclerosis, systemic lupus erythematosus (SLE), and Crohn’s disease.
    Toralizumab
  • HY-P99049
    Sotigalimab
    		Agonist 98.90%
    Sotigalimab, a CD40 agonistic monoclonal antibody. Sotigalimab binds CD40 with high affinity and activates antigen-presenting cells, thereby stimulating cancer-specific T cell responses. Sotigalimab is mainly used in the study of metastatic pancreatic cancer and metastatic melanoma.
    Sotigalimab
  • HY-123630
    Allura Red AC
    		Activator 98.01%
    Allura Red AC is a food colorant, appearing as a deep red water-soluble powder or granules, used in various applications such as beverages, syrups, candies, and cereals. Allura Red AC can statically quench the intrinsic fluorescence of HSA. Additionally, Allura Red AC is a 5-hydroxytryptamine (5-HT) pathway-associated pro-inflammatory agent, capable of exacerbating experimental colitis. Allura Red AC holds potential for research in inflammatory bowel disease (IBD), intestinal barrier function, and food additive safety.
    Allura Red AC
  • HY-139481
    TL-895
    		Inhibitor 99.86%
    TL-895 is a potent, orally active, ATP-competitive, and highly selective irreversible BTK inhibitor. TL-895 is active against recombinant BTK (average IC50: 1.5 nM) and inhibits only three additional kinases BLK, BMX (IC50 = 1.6 nM) and TXK with IC50 within tenfold of BTK activity. TL-895 inhibits BTK auto-phosphorylation at the Y223 phosphorylation site (IC50: 1-10 nM). The TL-895 effectively inhibits the production of inflammatory factors such as IL-8, IL-1β, MCP-1 and TNF-α by monocytes or macrophages, and reduces the chemotactic migration of MF cells towards SDF-1. TL-895 is used be for studies of chronic lymphocytic leukemia (CLL), myelofibrosis (MF), and B-cell malignancies.
    TL-895
  • HY-P99445
    Asunercept
    		Inhibitor 98.13%
    Asunercept (APG101; CAN008) is a soluble CD95-Fc fusion protein targeting CD95L. Asunercept disrupts CD95/CD95L signaling by selectively binding to CD95L. Asunercept can be used in the research of glioblastoma multiforme (GBM), myelodysplastic syndrome (MDS), and graft-versus-host disease (GvHD).
    Asunercept
  • HY-N0724
    Mesaconitine
    		Inhibitor 99.19%
    Mesaconitine is the main active component of genus aconitum plants.
    Mesaconitine
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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