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-P990070
    Zigakibart
    		Inhibitor 98.37%
    Zigakibart (BION-1301) is an IgG4-kappa, anti-TNFSF13 (tumor necrosis factor (TNF) superfamily member 13, APRIL, CD256) humanized monoclonal antibody. Zigakibart shows anti-inflammatory activity.
    Zigakibart
  • HY-154822
    DRI-C25441
    		Inhibitor 99.53%
    DRI-C25441 is a potent blocker of CD40 and CD40L interaction, with an IC50 of 0.36 μM. DRI-C25441 can inhibit the immune response induced by alloantigen.
    DRI-C25441
  • HY-N3595
    Cleomiscosin A
    		Inhibitor 99.15%
    Cleomiscosin A is a coumarino-lignoid from branch of Macaranga adenantha. Cleomiscosin A is active against TNF-alpha secretion of the mouse peritoneal macrophages.
    Cleomiscosin A
  • HY-117082
    UTL-5g
    		Inhibitor 99.92%
    UTL-5g (GBL-5g), an anti-inflammatory TNF-α inhibitor, has chemoprotective and liver radioprotective effects. UTL-5g lowers hepatotoxicity, nephrotoxicity, and myelotoxicity induced by Cisplatin through TNF-α inhibition among other factors.
    UTL-5g
  • HY-N2036
    Mosloflavone
    		99.19%
    Mosloflavone is a flavonoid isolated from Scutellaria baicalensis Georgi with ?anti-EV71 activity. Mosloflavone? inhibits VP2 virus replication and protein expression during the initial stage of virus infection and inhibits viral VP2 capsid protein synthesis. Mosloflavone is a promising biocide and inhibits P. aeruginosa virulence and biofilm formation.
    Mosloflavone
  • HY-P1860A
    TNF-α (31-45), human TFA
    		Activator
    TNF-α (31-45), human TFA is a potent NF-kB pathway activator. TNF-αis a proinflammatory cytokine that induces necrosis or apoptosis. TNF alpha stimulates NF-κB pathway via TNFR2 promotes cancer growth, invasion, and metastasis.
    TNF-α (31-45), human TFA
  • HY-B0190
    Nafamostat
    Nafamostat, an anticoagulant, is a synthetic serine protease inhibitor. Nafamostat has anticancer and antivirus effect. Nafamostat induce apoptosis by up-regulating the expression of tumor necrosis factor receptor-1 (TNFR1). Nafamostat can be used in the development of the pathological thickening of the arterial wall.
    Nafamostat
  • HY-P99821
    Ravagalimab
    		Inhibitor 99.31%
    Ravagalimab (ABBV-323) is a CD40 antagonist (EC50: 3.7 nM). Ravagalimab can be used for research of Crohn's disease.
    Ravagalimab
  • HY-P990018
    Boserolimab
    		Inhibitor 99.00%
    Boserolimab (MK-5890) is a humanized agonist monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell–mediated responses.
    Boserolimab
  • HY-P99057A
    Varlilumab (anti-CD27)
    		Inhibitor 98.65%
    Varlilumab (anti-CD27) is a first-in-class human IgG1 anti-CD27 monoclonal antibody. Varlilumab has an anti-tumor activity.
    Varlilumab (anti-CD27)
  • HY-P990067
    Evunzekibart
    		Inhibitor
    Evunzekibart (ATOR-1017) is an Fc-γ receptor conditional 4-1BB agonist and IgG4-type antibody. Evunzekibart can be used as monotherapy or in combination with anti-PD1 to exert anticancer activity.
    Evunzekibart
  • HY-P99605
    Cinrebafusp alfa
    		Inhibitor 98.53%
    Cinrebafusp alfa (PRS 343) is a high affinity CD137/HER2 bispecfic anticalin-based drug. Cinrebafusp alfa binds to recombinant human HER2 (Kd=0.3 nM) and human monomeric CD137 (4-1BB; Kd=5 nM). Cinrebafusp alfa facilitates T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation, further enhancing T-cell receptor-mediated activity and leading to tumor destruction. Cinrebafusp alfa has the potential for HER2+ solid tumors research.
    Cinrebafusp alfa
  • HY-P99321
    Teneliximab
    		Inhibitor ≥99.0%
    Teneliximab (BMS-224819) is a chimeric monoclonal antibody, blocks the CD40-CD40L interaction. Teneliximab (BMS-224819) has partial agonist activity resulting in some signaling through CD40 and peripheral B cell depletion.
    Teneliximab
  • HY-P990095
    Vonsetamig
    		Inhibitor
    Vonsetamig is a humanised immunoglobulin G4-kappa, anti-TNFRSF17 and CD3E monoclonal antibody. Vonsetamig is an antineoplastic.
    Vonsetamig
  • HY-N10913
    Chloranthalactone B
    		Inhibitor
    Chloranthalactone B, a lindenane-type sesquiterpenoid, is a nature product that could be isolated from Chinese medicinal herb Sarcandra glabra. Chloranthalactone B inhibits the production of inflammatory mediators by inhibiting the AP-1 and p38 MAPK pathways.
    Chloranthalactone B
  • HY-P99669
    Iratumumab
    		Inhibitor 98.95%
    Iratumumab (MDX-060) a human anti-CD30 IgG1κ monoclonal antibody. Iratumumab inhibits the growth of CD30-expressing tumor cells. Iratumumab can be used for research of Hodgkin's lymphoma (HL) and anaplastic large-cell lymphoma (ALCL).
    Iratumumab
  • HY-101170
    BU224 hydrochloride
    		Inhibitor
    BU224 hydrochloride is a selective and high affinity imidazoline I2 receptor ligand, with a Ki of 2.1 nM. BU224 hydrochloride is sometimes used as an I2 receptor antagonist. BU224 hydrochloride exerts neuroprotective effects, with anti-inflammatory and anti-apoptotic properties. BU224 hydrochloride improves memory in 5XFAD mice, enlarging dendritic spines and reducing Aβ-induced changes in NMDARs. BU224 hydrochloride can be used for Alzheimer's disease research.
    BU224 hydrochloride
  • HY-106359A
    Delmitide acetate
    		Inhibitor 98.55%
    Delmitide (RDP58) acetate is an orally active d-isomer decapeptide with potent anti-inflammatory activity. Delmitide acetate inhibits production of TNF-α, IFN-γ, and interleukin (IL)-12, and up-regulates heme oxygenase 1 activity. Delmitide acetate can be used for the research of ulcerative colitis.
    Delmitide acetate
  • HY-N6927
    Isoforskolin
    		Inhibitor ≥98.0%
    Isoforskolin is the principle active component of C. forskohlii native to China. Isoforskolin reduces the secretion of lipopolysaccharide (LPS)-induced cytokines, namely TNF-α, IL-1β, IL-6 and IL-8, in human mononuclear leukocytes. Isoforskolin acts as an anti-inflammatory agent for the treatment of Lyme arthritis.
    Isoforskolin
  • HY-P3149B
    LEESGGGLVQPGGSMK acetate
    		99.01%
    LEESGGGLVQPGGSMK acetate, a proteolysis peptide, is a component of Infliximab. LEESGGGLVQPGGSMK acetate can be used for quantitative analysis of Infliximab. Infliximab is a chimeric monoclonal IgG1 antibody that specifically binds to TNF-α.
    LEESGGGLVQPGGSMK acetate
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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