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-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-P990706
    Povetacicept
    		Inhibitor 99.9%
    Povetacicept (ALPN-303) is an engineered Fc fusion protein containing the TACI domain, and acts as a dual APRIL/BAFF antagonist. The Kd value of Povetacicept for human BAFF is 59.3 pM, while its Kd value for human APRIL is 1.00 pM. Povetacicept reduces the activation, proliferation, differentiation and survival of B cells, and inhibits the production of immunoglobulins and autoantibodies. Povetacicept can be used in research related to autoimmune hemolytic anemia, immune thrombocytopenia, systemic lupus erythematosus, lupus nephritis and myasthenia gravis.
    Povetacicept
  • HY-N6796
    Manumycin A
    		Inhibitor 99.27%
    Manumycin A is a polyketide antibiotic and an inhibitor of thioredoxin reductase 1 (TrxR-1). Manumycin A can inhibit the growth of breast cancer cells and exert its anti-tumor activity through LC3. Manumycin A can downregulate the release of pro-inflammatory cytokines in human monocytes stimulated by TNF α, and has potential anti-inflammatory activity. Manumycin A can inhibit the Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration resistant prostate cancer cells to suppress exosome biogenesis and secretion.
    Manumycin A
  • HY-138113
    Pyrrothiogatain
    		Inhibitor 98.61%
    Pyrrothiogatain is a transcription factor GATA3 inhibitor with an IC50 of 54.7 μM. Pyrrothiogatain inhibits the DNA-binding activity of GATA3 and inhibits the T helper 2 (Th2) cell differentiation and expression of Th2 cytokines. Pyrrothiogatain shows anti-infection effect by inhibiting ACE2 expression. Pyrrothiogatain can be used for the researches of inflammation, immunology, infection and cancer, such as colon cancer and SARS-CoV-2 infection.
    Pyrrothiogatain
  • 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-134471
    TNF-α-IN-2
    		Inhibitor 99.2%
    TNF-α-IN-2 is a potent and orally active inhibitor of tumor necrosis factor alpha (TNFα), with an IC50 of 25 nM in the HTRF assay. TNF-α-IN-2 distorts the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNFR1. TNF-α-IN-2 can be used for the research of rheumatoid arthritis.
    TNF-α-IN-2
  • HY-122663A
    BIO8898
    		Inhibitor 98.77%
    BIO8898 is a potent CD40-CD154 inhibitor. BIO8898 inhibits soluble CD40L binding to CD40-Ig with an IC50 value of 25 µM. BIO8898 inhibits CD40L-induced apoptosis.
    BIO8898
  • HY-N0472
    Geraniin
    		Inhibitor 99.82%
    Geraniin is a TNF-α releasing inhibitor with numerous activities including anticancer, anti-inflammatory, and anti-hyperglycemic activities, with an IC50 of 43 μM.
    Geraniin
  • HY-P9953
    Certolizumab pegol
    		Inhibitor 99.30%
    Certolizumab pegol (Certolizumab) is a recombinant, polyethylene glycosylated, antigen-binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes tumour necrosis factor-α (TNF-α). Certolizumab pegol can be used for rheumatoid arthritis and Crohn disease research.
    Certolizumab pegol
  • HY-N0633
    Muscone
    		Inhibitor 98.0%
    Muscone is the main active monomer of traditional Chinese medicine musk. Muscone inhibits NF-κB and NLRP3 inflammasome activation. Muscone remarkably decreases the levels of inflammatory cytokines (IL-1β, TNF-α and IL-6), and ultimately improves cardiac function and survival rate.
    Muscone
  • HY-P99446
    Atacicept
    		Inhibitor 99.5%
    Atacicept (TACI-Ig) is a is a recombinant fusion protein containing the extracellular, ligand-binding portion of the TACI receptor and the Fc portion of human IgG. Atacicept inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferation-inducing ligand. Atacicept can be used in research of B-cell autoimmune disease.
    Atacicept
  • HY-113556
    Sappanone A
    		Inhibitor 99.87%
    Sappanone A is an orally active homoisoflavone found in sappan L. Sappanone A is a PDE4 and NF-κB inhibitor with anti-inflammatory and antioxidant effect. Sappanone A induces HO-1 expression through activation of Nrf2 pathway. Sappanone A also inhibits RANKL-induced osteoclastogenesis. Sappanone A has great potential in the research of inflammation-related and cardiovascular .
    Sappanone A
  • HY-147141
    HS-276
    		Inhibitor 98.93%
    HS-276 is an orally active, potent and highly selective TAK1 inhibitor, with a Ki of 2.5 nM. HS-276 shows significant inhibition of TAK1, CLK2, GCK, ULK2, MAP4K5, IRAK1, NUAK, CSNK1G2, CAMKKβ-1, and MLK1, with IC50 values of 8.25, 29, 33, 63, 125, 264, 270, 810, 1280, and 5585 nM, respectively. HS-276 reduces the expression of TNF, IL-6, and IL-1β. HS-276 can be used for rheumatoid arthritis (RA) research.
    HS-276
  • HY-12220
    MM-102
    		Inhibitor 99.09%
    MM-102 (HMTase Inhibitor IX) is a cell-permeable and tightly binding inhibitor of MLL1-WDR5 interaction (IC50=2.4 nM). MM-102 can specifically inhibit the growth and induce apoptosis of leukemia cells containing MLL1 fusion protein, and reduce renal fibrosis and inflammation in mice with ischemia-reperfusion injury. In addition, MM-102 also acts as an H3K4 histone methyltransferase inhibitor to improve the development of porcine somatic cell nuclear transfer (SCNT) embryos.
    MM-102
  • HY-120323
    DRI-C21045
    		Inhibitor 98.11%
    DRI-C21045 (compound 10) is a potent and selective inhibitor of the CD40-CD40L costimulatory protein-protein interaction (PPI) with an IC50 of 0.17 μM. DRI-C21045 shows concentration-dependent inhibition of the activation of NF-κB and B cell proliferation all induced by CD40L with IC50s of 17.1 μM and 4.5 μM, respectively.
    DRI-C21045
  • HY-N0604
    Ginsenoside Rh1
    		Inhibitor 98.72%
    Ginsenoside Rh1 (Prosapogenin A2) inhibits the expression of PPAR-γ, TNF-α, IL-6, and IL-1β.
    Ginsenoside Rh1
  • 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-N0448
    10-Gingerol
    		Inhibitor 99.48%
    10-Gingerol is an AMPK agonist, which is found in the ginger oleoresin from fresh rhizome with anti-inflammatory, antioxidant and anti-proliferative activities. 10-Gingerol suppresses neointimal hyperplasia and inhibits vascular smooth muscle cell proliferation. 10-Gingerol exhibits substantial scavenging activities with an IC50 value of 10.47 μM against DPPH radical, an IC50 value of 1.68 μM against superoxide radical and an IC50 value of 1.35 μM against hydroxyl radical. 10-Gingerol inhibits the proliferation of MDA-MB-231 tumor cell line with an IC50 of 12.1 μM. 10-Gingerol suppresses the proliferation, migration, invasion, and induced apoptosis through targeting the PI3K/Akt signaling pathway in MDA-MB-231/IR cells. 10-Gingerol can be used in research on various common cancers such as ovarian cancer and colon cancer, as well as colitis and neurodegenerative diseases.
    10-Gingerol
  • HY-N0569
    Madecassic acid
    		Inhibitor 99.93%
    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-114360
    Taurohyodeoxycholic acid
    		Inhibitor 99.73%
    Taurohyodeoxycholic acid is an orally active 6 alpha-hydroxylated bile acid. Taurohyodeoxycholic acid decreases colonic MPO activity, TNF-α, lL-6 serum levels and the expression of COX-2. Taurohyodeoxycholic acid alleviates trinitrobenzene sulfonic acid induced ulcerative colitis via regulating Th1/Th2 and Th17/Treg cells balance. Taurohyodeoxycholic acid ameliorates high-fat diet-induced nonalcoholic fatty liver disease in mice. Taurohyodeoxycholic acid prevents Taurochenodeoxycholic acid (HY-N2027)-induced hepatotoxicity in bile fistula rats. Taurohyodeoxycholic acid can be used for the study of nonalcoholic fatty liver disease (NAFLD), colitis and biliary fistula.
    Taurohyodeoxycholic 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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