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-B1051
    Flumethasone
    		Inhibitor 99.84%
    Flumethasone (Flumetasone) is an orally active, high selective and potent glucocorticoid receptor (GR) agonist. Flumethasone activates GR to inhibit nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokine production (TNF-α, IL-1β) and promotes anti-inflammatory gene expression (IL-10), while also regulating metabolic enzyme activity (tyrosine aminotransferase induction). Flumethasone is promising for research of inflammatory diseases, cancer, and endocrine regulation.
    Flumethasone
  • HY-P99315
    Ruplizumab
    		Inhibitor 99.84%
    Ruplizumab (BG 9588) is a humanized anti-CD40L IgG1κ monoclonal antibody. By binding to CD40L, Ruplizumab blocks its interaction with the CD40 receptor, inhibits T-B cell costimulatory signals, and mediates the depletion of activated T cells via the Fc segment. Ruplizumab has immunosuppressive effects. Ruplizumab can be used in the study of systemic lupus erythematosus, organ transplant rejection, and autoimmune diseases. Recommend Isotype Controls: Human IgG1 kappa, Isotype Control (HY-P99001).
    Ruplizumab
  • HY-P9970A
    Infliximab (Anti-TNF-α)
    		Inhibitor 99.00%
    Infliximab (Anti-TNF-α) (Avakine (Anti-TNF-α)) is a chimeric monoclonal IgG1 antibody that specifically binds to TNF-α. Infliximab (Anti-TNF-α) prevents the interaction of TNF-α with TNF-α receptor (TNFR1 and TNFR2). Infliximab (Anti-TNF-α) has the potential for autoimmune, chronic inflammatory diseases and diabetic neuropathy research.
    Infliximab (Anti-TNF-α)
  • HY-P99249
    Vonlerolizumab
    		Inhibitor 99.70%
    Vonlerolizumab (MOXR 0916) is a humanized IgG agonistic monoclonal OX40-specific antibody. Vonlerolizumab can be used for the research of cancer.
    Vonlerolizumab
  • HY-139066
    Punicic acid
    		Inhibitor ≥98.0%
    Punicic acid is a bioactive compound of pomegranate seed oil. Punicic acid is an isomer of conjugated α-linolenic acid and ω-5 polyunsaturated fatty acids. Punicic acid has anti-inflammatory and antioxidant activities and can inhibit the expression of inflammatory mediators such as tumor necrosis factor α (TNF-α). Punicic acid can also reduce the formation of β-amyloid deposits and hyperphosphorylation of tau by increasing the expression of GLUT4 protein and inhibiting the overactivation of calpain, and is used to prevent and treat neurodegenerative diseases. In addition, punicic acid also has breast cancer inhibitor properties that depend on lipid peroxidation and PKC pathways.
    Punicic acid
  • 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-118922
    IW927
    		Antagonist 99.04%
    IW927 is a potent small molecule antagonist that blocks the binding of TNF-α to TNFRc1 with an IC50 value of 50 nM and disrupts TNFα-induced IκB phosphorylation with an IC50 value of 600 nM.
    IW927
  • HY-15507
    VGX-1027
    		Inhibitor 99.76%
    VGX-1027 is an orally active isoxazole compound that exhibits various immunomodulatory properties. VGX-1027 targets macrophages, reducing the production of the proinflammatory mediators TNF-α, IL-1β, IL-10. VGX-1027 has antidiabetogenic effects by limiting cytokine-mediated immunoinflammatory events.
    VGX-1027
  • HY-135674
    SR-318
    		Inhibitor 99.89%
    SR-318 is a potent and highly selective p38 MAPK inhibitor with IC50s of 5 nM, 32 nM and 6.11 μM for p38α, p38β and p38α/β, respectively. SR-318 potently inhibits the TNF-α release in whole blood with an IC50 of 283 nM. SR-318 has anti-cancer and anti-inflammatory activity.
    SR-318
  • 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-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-P99149
    Anti-Mouse TNFR2 Antibody (TR75-54.7)
    		Inhibitor
    Anti-Mouse TNFR2 Antibody is an anti-mouse TNFR2 IgG antibody inhibitor derived from host Armenian Hamster.
    Anti-Mouse TNFR2 Antibody (TR75-54.7)
  • HY-19667A
    BMS-561392 formate
    		Inhibitor 99.38%
    BMS-561392 formate is the formate form of BMS-561392 (HY-19667). BMS-561392 is a TNF alpha-converting enzyme (TACE) inhibitor. BMS-561392 is also an ADAM17 blocker. BMS-561392 can be used for research of inflammatory bowel disease.
    BMS-561392 formate
  • HY-N1887
    4-Allylcatechol
    		Inhibitor 99.73%
    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-132248
    C5 Lenalidomide
    		Inhibitor 99.62%
    C5 Lenalidomide (Lenalidomide 5'-amine) is a thalidomide analog and is a potent inhibitor of TNF-alpha production (IC50=100 μM in LPS stimulated human PBMC).
    C5 Lenalidomide
  • HY-18377
    Bioymifi
    		Activator ≥98.0%
    Bioymifi (DR5 Activator), a potent TRAIL receptor DR5 activator, binds to the extracellular domain (ECD) of DR5 with a Kd of 1.2 μM. Bioymifi can act as a single agent to induce DR5 clustering and aggregation, leading to apoptosis.
    Bioymifi
  • HY-W012732
    Isoquinoline
    		Inhibitor 99.58%
    Isoquinoline is an analog of pyridine. Isoquinoline-based alkaloids, such as p-tolyl bisisoquinoline, phthaloyl isoquinoline, and naphthyl isoquinoline, exhibit anticancer activity. Berberine, an isoquinoline alkaloid, exerts anti-inflammatory effects in diabetic mice by downregulating the gene expression ratios of pro-/anti-inflammatory and Th1/Th2 cytokines. Additionally, some isoquinoline-based compounds also possess antidepressant, antibacterial, antimalarial, and anti-HIV activities.
    Isoquinoline
  • HY-P99167
    Lucatumumab
    		Inhibitor 98.18%
    Lucatumumab (HCD122) is a fully human anti-CD40 antagonist monoclonal antibody, which blocks CD40/CD40L-mediated signaling. Lucatumumab efficiently mediates antibody-dependent cell-mediated cytotoxicity (ADCC) and clearance of tumor cells, can be used for refractory lymphomas, CLL and multiple myeloma research.
    Lucatumumab
  • HY-P99220
    Tabalumab
    		Inhibitor 98.11%
    Tabalumab (LY2127399) is a human anti-BAFF (B-cell activating factor) monoclonal antibody (IgG4 type) with neutralising activity against membrane bound and soluble BAFF. Tabalumab can be used in studies of autoimmune diseases such as rheumatoid arthritis, renal failure and systemic lupus erythematosus.
    Tabalumab
  • HY-P99812
    Ragifilimab
    		Agonist ≥99.0%
    Ragifilimab (INCAGN-1876) is an agonist monoclonal antibody targeting the glucocorticoid-induced TNFR-related protein (GITR). Ragifilimab can be used for advanced or metastatic solid tumors research.
    Ragifilimab
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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