1. Signaling Pathways
  2. Apoptosis
  3. TNF Receptor

TNF Receptor

Tumor Necrosis Factor Receptor; TNFR

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.

Cat. No. Product Name Effect Purity Chemical Structure
  • HY-P991513
    BI-655064
    Inhibitor 98.56%
    BI-655064, a humanised anti-CD40 antibody with has fragment crystallisable (Fc) regions with two mutations that prevent Fc-mediated antibody-dependent or complement-mediated cellular cytotoxicity and platelet activation. BI-655064 can be used for the study of autoimmune disease, such as lupus nephritis and rheumatoid arthritis (RA).
    BI-655064
  • HY-N2855
    Alphitolic acid
    Inhibitor
    Alphitolic acid (Aophitolic acid) is an anti-inflammatory triterpene could found in quercus aliena. Alphitolic acid blocks Akt–NF-κB signaling to induce apoptosis. Alphitolic acid induces autophagy. Alphitolic acid has anti-inflammatory activity and down-regulates the NO and TNF-α production. Alphitolic acid can be used for cancer and inflammation research.
    Alphitolic acid
  • HY-15790H
    (S)-Elobixibat
    Inhibitor 98.75%
    (S)-Elobixibat is the S enantiomer of Elobixibat (HY-15790). (S)-Elobixibat is an orally effective Apical Sodium-Dependent Bile (IBAT) inhibitor. (S)-Elobixibat decreases LDL cholesterol, increases serum GLP-1, promotes colon motility, and has the potential to study metabolic syndrome. (S)-Elobixibat can be used to study constipation, dyslipidemia, non-alcoholic hepatitis, and liver tumors.
    (S)-Elobixibat
  • HY-N1904
    4′-Hydroxywogonin
    Inhibitor 98.22%
    4′-Hydroxywogonin (8-Methoxyapigenin), a flavonoid, could be isolated from a variety of plants including Scutellaria barbata and Verbena littoralis. 4′-Hydroxywogonin has anti-inflammatory activity via TAK1/IKK/NF-κB, MAPKs and PI3/AKT signaling pathways. 4′-Hydroxywogonin inhibits angiogenesis by disrupting PI3K/AKT signaling. 4′-Hydroxywogonin inhibits cell proliferation and induces apoptosis.
    4′-Hydroxywogonin
  • HY-P990778
    Xirestomig
    Inhibitor 98.44%
    Xirestomig (ATG-101) is a tetravalent "2+2″ PD-L1×4-1BB bispecific antibody. Xirestomig binds PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when cross-linked with PD-L1-positive cells. Xirestomig activates exhausted T cells upon PD-L1 binding. Xirestomig displays potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to immune checkpoint inhibitors (ICIs).
    Xirestomig
  • HY-158990
    GE1111
    Inhibitor
    GE1111 is a MRGPRX2 antagonist (IC50 = 9.4 μM). GE1111 inhibits MRGPRX2/MRGPRB2-mediated mast cell activation. GE1111 reduces the expressions of TSLP, IL-13, MCP-1, TNF-α, IL-1β and periostin, maintains the expression levels of claudin 1 and involucrin, restores the phagocytic activity of macrophages, and attenuates the activation of STIM1 and phosphorylated AKT. GE1111 exerts anti-inflammatory and anti-allergic effects in multiple animal models. GE1111 is applicable to the research related to rosacea, atopic dermatitis and ulcerative colitis.
    GE1111
  • HY-N0182A
    Fisetin quarterhydrate
    Inhibitor
    Fisetin quarterhydrate is a natural flavonol found in many fruits and vegetables with various benefits, such as antioxidant, anticancer, neuroprotection effects.
    Fisetin quarterhydrate
  • HY-N8371
    Shizukaol B
    Inhibitor
    Shizukaol B is a lindenane-type dimeric sesquiterpene, used to be isolated from the whole plant of Chloranthus henryi. Shizukaol B has anti-inflammatory effect against lipopolysaccharide (LPS)-induced activation of BV2 microglial cells. Shizukaol B inhibits iNOS and COX-2, and suppresses NO production, TNF-α, and IL-1β expression.
    Shizukaol B
  • HY-N0297R
    Sinensetin (Standard)
    Inhibitor
    Sinensetin (Standard) is the analytical standard of Sinensetin. This product is intended for research and analytical applications.
    Sinensetin (Standard)
  • HY-N0822R
    Shikonin (Standard)
    Inhibitor
    Shikonin (Standard) is the analytical standard of Shikonin. This product is intended for research and analytical applications. Shikonin is a major component of a Chinese herbal medicine named zicao. Shikonin is a potent TMEM16A chloride channel inhibitor with an IC50 of 6.5 μM. Shikonin is a specific pyruvate kinase M2 (PKM2) inhibitor and can also inhibit TNF-α and NF-κB pathway. Shikonin decreases exosome secretion through the inhibition of glycolysis. Shikonin inhibits AIM2 inflammasome activation.
    Shikonin (Standard)
  • HY-W015490S
    1,4-Naphthoquinone-d6
    Inhibitor 99.20%
    1,4-Naphthoquinone-d6 is the deuterium labeled 1,4-Naphthoquinone. 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-d<sub>6</sub>
  • HY-N0722R
    Neochlorogenic acid (Standard)
    Inhibitor
    Neochlorogenic acid (Standard) is the analytical standard of Neochlorogenic acid. This product is intended for research and analytical applications. Neochlorogenic acid is a natural polyphenolic compound found in dried fruits and other plants. Neochlorogenic acid inhibits the production of TNF-α and IL-1β. Neochlorogenic acid suppresses iNOS and COX-2 protein expression. Neochlorogenic acid also inhibits phosphorylated NF-κB p65 and p38 MAPK activation.
    Neochlorogenic acid (Standard)
  • HY-B0898R
    Ceftiofur sodium (Standard)
    Inhibitor
    Ceftiofur sodium (Standard) is the analytical standard of Ceftiofur sodium (HY-B0898). This product is intended for research and analytical applications. Ceftiofur sodium is a cell wall synthesis inhibitor that targets bacterial penicillin-binding proteins (PBPs) and has anti-inflammatory effects in endotoxemia. Ceftiofur sodium exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycan, leading to bacterial cell lysis. Ceftiofur sodium also inhibits the activation of NF-κB and MAPKs, thereby reducing the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6.
    Ceftiofur sodium (Standard)
  • HY-W013636C
    2-Ketoglutaric acid potassium
    Inhibitor 98.0%
    2-Ketoglutaric acid (Alpha-Ketoglutaric acid) (potassium) is an intermediate in the production of ATP or GTP in the Krebs cycle. 2-Ketoglutaric acid potassium is a reversible and orally active inhibitor of tyrosinase with an IC50 value of 15 mM. 2-Ketoglutaric acid potassium also acts as the major carbon skeleton for nitrogen-assimilatory reactions. 2-Ketoglutaric acid potassium significantly suppresses abnormal intestinal permeability, delocalization of tight junction proteins from the intestinal cells, expression of TNFα in vitro and in vivo. 2-Ketoglutaric acid potassium directly binds to TAK1, and inhibits the TRAF6-TAK1 interaction. 2-Ketoglutaric acid potassium also alleviates inflammatory bowel disease (IBD) symptoms and gut microbiota dysbiosis, evident by the improvements in the intestine length.
    2-Ketoglutaric acid potassium
  • HY-W013331
    Deoxyartemisinin
    Inhibitor 99.9%
    Deoxyartemisinin (2-Deoxyartemisinin) is an orally active anti-inflammatory and analgesic agent. Deoxyartemisinin selectively reduces the level of the pro-inflammatory cytokine TNF-α. Deoxyartemisinin alleviates neuropathic pain, inflammatory pain, and croton oil-induced ear edema.\nDeoxyartemisinin exerts an analgesic effect against thermal stimulation. Deoxyartemisinin has anti-ulcer activity. Deoxyartemisinin can be used in research related to inflammatory diseases, pain, and gastric ulcers.
    Deoxyartemisinin
  • HY-P991014
    Pamlectabart
    Inhibitor
    HY-P991014 is an TNFRSF17-targeting IgG1κ type humanized antibody, the recommed isotype control is Human IgG1 kappa, Isotype Control (HY-P99001).
    Pamlectabart
  • HY-164893
    ABBV-154
    Inhibitor
    ABBV-154 is an anti-TNF antibody-drug conjugate (ADC). ABBV-154 is composed of the humanized antibody Adalimumab (HY-P9908) conjugated with a glucocorticoid receptor modulator (HY-137883). ABBV-154 can be used in studies of rheumatoid arthritis, Crohn's disease and polymyalgia rheumatica.
    ABBV-154
  • HY-P991024
    Solabafusp alfa
    Inhibitor
    HY-P991024 is an CD274/TNFRSF9-targeting IgG4κ type humanized antibody, the recommed isotype control is Human IgG4 (S228P) kappa, Isotype Control (HY-P99003).
    Solabafusp alfa
  • HY-P991012
    Nuvustotug
    Inhibitor
    HY-P991012 is an TNFRSF4-targeting IgG1κ type human antibody, the recommed isotype control is Human IgG1 kappa, Isotype Control (HY-P99001).
    Nuvustotug
  • HY-P990971
    Atenastobart
    Inhibitor 98.473%
    HY-P990971 is an TNFRSF9-targeting IgG1λ2 type human antibody, the recommed isotype control is Human IgG1 lambda2, Isotype Control (HY-P990096).
    Atenastobart
Cat. No. Product Name / Synonyms Species Source
Cat. No. Product Name / Synonyms Application Reactivity

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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