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-N0368
    Linalool
    		98.55%
    Linalool is a natural monoterpene which is a competitive NMDA receptor antagonist. Linalool is orally active and crosses the blood-brain barrier. Linalool has anticancer, antibacterial, anti-inflammatory, neuroprotective, anxiolytic, antidepressant, anti-stress, cardioprotective, hepatoprotective, nephroprotective and pulmonary protective activities.
    Linalool
  • HY-101849
    Fasentin
    		Agonist ≥98.0%
    Fasentin, a potent glucose uptake inhibitor, inhibits GLUT-1/GLUT-4 transporters. Fasentin preferentially inhibits GLUT4 (IC50=68 μM) over GLUT1. Fasentin is a death receptor stimuli (FAS) sensitizer and sensitizes cells to FAS-induced cell death. Fasentin is also a tumor necrosis factor (TNF) apoptosis-inducing ligand sensitizer. Fasentin blocks glucose uptake in cancer cell lines and has anti-angiogenic activity.
    Fasentin
  • HY-N2195
    Nootkatone
    		Inhibitor 99.81%
    Nootkatone, a neuroprotective agent from Vitis vinifera, has antioxidant and anti-inflammatory effects. Nootkatone improves cognitive impairment in lipopolysaccharide-induced mouse model of Alzheimer's disease.
    Nootkatone
  • HY-A0059
    Nifuratel
    		99.93%
    Nifuratel (NF 113) is an orally active broad-spectrum antibiotic with antiprotozoal, antibacterial, anticancer and anti-inflammatory activities, and has good inhibitory effects on Candida and Trichomonas. Nifuratel is also a STAT3 inhibitor, which significantly inhibits the growth and proliferation of human gastric cancer cells and induces apoptosis. In addition, Nifuratel also inhibits mast cell-mediated antigen hypersensitivity reactions and can be used in the study of IgE-mediated allergic diseases.
    Nifuratel
  • HY-P99260
    Conatumumab
    		Agonist 98.90%
    Conatumumab (AMG 655) is a human monoclonal agonist antibody against human death receptor 5 (DR5, TRAILR2) (Kd: 1 nM for the long form of DR5, 0.8 nM for the short form of DR5). Conatumumab induces apoptosis via caspase activation. Conatumumab can be used in the research of cancers. .
    Conatumumab
  • HY-B1201
    Tiratricol
    		Inhibitor 98.88%
    Tiratricol is an orally available thyroid hormone analog that inhibits pituitary thyroid-stimulating hormone secretion. Tiratricol is an intracellular toxin neutralizer that inhibits LPS and lipid A cytotoxicity with IC50s of 20 μM and 32 μM, respectively. Tiratricol reduces TNF production in lipopolysaccharide-stimulated macrophages. Tiratricol also has antiviral activity and is an inhibitor of yellow fever virus (Flavivirus). It can bind to the RdRp domain of the viral NS5 protein to hinder YFV replication..
    Tiratricol
  • HY-N6739
    Beauvericin
    		99.97%
    Beauvericin is a cyclohexapeptide Fusarium toxin with insecticidal, antibacterial, anticancer, antiviral and cytotoxic activities. Beauvericin causes cellular genotoxicity by producing DNA breaks, chromosomal aberrations and micronuclei, and inhibits the PI3K/AKT pathway to induce apoptosis, thereby inhibiting the growth of HCC. In addition, Beauvericin affects immune function by inhibiting lymphocyte proliferation and interfering with the differentiation process of human monocytes into macrophages.
    Beauvericin
  • HY-N1949
    Homoplantaginin
    		Inhibitor 99.90%
    Homoplantaginin is a flavonoid from a traditional Chinese medicine Salvia plebeia with antiinflammatory and antioxidant properties. Homoplantaginin could inhibit TNF-α and IL-6 mRNA expression, IKKβ and NF-κB phosphorylation.
    Homoplantaginin
  • HY-N0604
    Ginsenoside Rh1
    		Inhibitor ≥98.0%
    Ginsenoside Rh1 (Prosapogenin A2) inhibits the expression of PPAR-γ, TNF-α, IL-6, and IL-1β.
    Ginsenoside Rh1
  • HY-150725
    ODN 1585
    		Inducer
    ODN 1585 is a potent inducer of IFN and TNFα production. ODN 1585 is a potent stimulator of NK (natural killer) function. ODN 1585 increases CD8+ T-cell function, including the CD8+ T cell-mediated production of IFN-γ. ODN 1585 induces regression of established melanomas in mice. ODN 1585 can confer complete protection against malaria in mice. ODN 1585 can be used for acute myelogenous leukemia (AML) and malaria research. ODN 1585 can be used as a vaccine adjuvant.
    ODN 1585
  • HY-P1068
    Lysozyme
    		Inhibitor
    Lysozyme (Muramidase) is a conserved antimicrobial protein. Lysozyme exerts its bactericidal effect by hydrolyzing bacterial cell wall peptidoglycan (PG). Lysozyme plays an important role in limiting bacterial growth on mucosal surfaces and other sites, not only controlling potential pathogens but also limiting overgrowth of microbiota to prevent dysbiosis. Extracellular lysozyme can also degrade polymeric PG into soluble fragments, activate NOD receptors in mucosal epithelial cells, and lead to the secretion of chemokines and activating factors by neutrophils and macrophages.
    Lysozyme
  • HY-100755
    KR-33493
    		Inhibitor 99.94%
    KR-33493 is a potent inhibitor of Fas-mediated cell death (FAF1).
    KR-33493
  • HY-N2350
    Cynaropicrin
    		Inhibitor 99.79%
    Cynaropicrin is a sesquiterpene lactone which can inhibit tumor necrosis factor (TNF-α) release with IC50s of 8.24 and 3.18 μM for murine and human macrophage cells, respectively. Cynaropicrin also inhibits the increase of cartilage degradation factor (MMP13) and suppresses NF-κB signaling.
    Cynaropicrin
  • HY-N0512
    Loganin
    		Inhibitor 99.85%
    Loganin is a type of iridoid glycoside compound that possesses anti-inflammatory, antioxidant, and antitumor properties, and offers protective effects against acute lung injury and pulmonary fibrosis. Loganin exerts its protective effects against LPS (HY-D1056)-mediated inflammation and oxidative stress by upregulating the Nrf2/HO-1 signaling pathway, and it reduces neuroinflammation caused by spinal cord injury (SCI).
    Loganin
  • HY-N2119
    Sciadopitysin
    		≥99.0%
    Sciadopitysin is a type of biflavonoids in leaves from ginkgo biloba. Sciadopitysi inhibits RANKL-induced osteoclastogenesis and bone loss by inhibiting NF-κB activation and reducing the expression of c-Fos and NFATc1.
    Sciadopitysin
  • HY-N0569
    Madecassic acid
    		Inhibitor 99.81%
    Madecassic acid is isolated from Centella asiatica (Umbelliferae). Madecassic acid has anti-inflammatory properties caused by iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 inhibition via the downregulation of NF-κB activation in RAW 264.7 macrophage cells.
    Madecassic acid
  • HY-101448
    TMI-1
    		Inhibitor 99.59%
    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-15509A
    Semapimod tetrahydrochloride
    		Inhibitor 98.43%
    Semapimod tetrahydrochloride (CNI-1493), an inhibitor of proinflammatory cytokine production, can inhibit TNF-α, IL-1β, and IL-6. Semapimod tetrahydrochloride inhibits TLR4 signaling (IC50≈0.3 μM). Semapimod tetrahydrochloride inhibits p38 MAPK and nitric oxide production in macrophages. Semapimod tetrahydrochloride has potential in a variety of inflammatory and autoimmune disorders.
    Semapimod tetrahydrochloride
  • HY-107390
    AX-024
    		Inhibitor 99.29%
    AX-024 is an orally available, first-in-class inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 ~1 nM. AX-024 modulates cell signaling by targeting SH3 domains. AX-024 has low-acute toxicity and high potency and selectivity, and strongly inhibit the production of IL-6, TNF-α, IFN-γ, IL-10 and IL-17A.
    AX-024
  • HY-P99670
    Iscalimab
    		Inhibitor 99.64%
    Iscalimab (CFZ-533) is a non-depleting IGg1 monoclonal antibody targeting CD40 (KD: 0.3 nM). Iscalimab can be used for research of Graves' hyperthyroidism and autoimmune diseases.
    Iscalimab
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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