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-P991180
    TRX-518
    		Ligand
    TRX-518 is a humanized agonist antibody targeting glucocorticoid-induced tumor necrosis factor receptor (GITR). TRX-518 specifically targets GITR⁺ Tregs and CD45RA⁻Foxp3⁺ effector Tregs (eTregs) among regulatory T cells (Tregs), reducing the number of Tregs in circulation and within tumors. TRX-518 is promising for research of cancers.
    TRX-518
  • 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-N13184
    Giraldoid B
    		Inhibitor 98.49%
    Giraldoid B is an active ingredient that can be isolated from Girald Daphne Bark. Giraldoid B can inhibit LPS induced NO and b>TNF-α production in RAW264.7 and has anti-inflammatory activity.
    Giraldoid B
  • HY-158650
    10-OAHSA
    		Inhibitor
    10-OAHSA is one of fatty acid esters of hydroxy fatty acids (FAHFAs). 10-POHSA increases glucose-stimulated insulin secretion (GSIS) at a high glucose concentration. 10-OAHSA reduces LPS (HY-D1056)-induced Tnf-α secretion in bone marrow-derived dendritic cells (BMDCs).
    10-OAHSA
  • HY-W026772S1
    Fluorene-d8
    Fluorene-d8 is the deuterium labeled Fluorene (HY-W026772). Fluorene is an orally active polycyclic aromatic hydrocarbon (PAH) and a precursor to other fluorene-based compounds. Fluorene and its derivatives serve as dye precursors for fluorene synthesis. In A549 cells, Fluorene induces oxidative stress and inflammatory responses by increasing ROS and SOD generation, exacerbating lipid peroxidation, modulating antioxidant enzyme activity, and upregulating the expression of pro-inflammatory factors TNF-α and IL-6. In vivo, Fluorene exhibits anxiolytic activity. Fluorene holds potential for research in inflammation and neurological disorders.
    Fluorene-d<sub>8</sub>
  • HY-W753791
    (±)-Perillaldehyde
    		Inhibitor
    (±)-Perillaldehyde has an antidepressant effect by modulating the olfactory nervous system in a mouse model of stress-induced depression. (±)-Perillaldehyde also has anti-inflammatory activity, inducing JNK activation in RAW264.7 cells and inhibiting the expression of TNF-α, with an IC50 of 171.7 μM.
    (±)-Perillaldehyde
  • HY-B0190B
    Nafamostat hydrochloride
    Nafamostat hydrochloride, an anticoagulant, is a synthetic serine protease inhibitor. Nafamostat hydrochloride has anticancer and antivirus effect. Nafamostat hydrochloride induces apoptosis by up-regulating the expression of tumor necrosis factor receptor-1 (TNFR1). Nafamostat hydrochloride can be used in the development of the pathological thickening of the arterial wall.
    Nafamostat hydrochloride
  • HY-P991179
    MK-4166
    		Agonist 98.20%
    MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. MK-4166 enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes.
    MK-4166
  • HY-P991178
    BMS-986156
    		Agonist
    BMS-986156 is a fully humanized IgG1 agonist monoclonal antibody agonist corticosteroid-induced tumor necrosis factor receptor-related protein (GITR). BMS-986156 binds to GITR and promotes activation of T effector cells and inactivates T regulatory cells. BMS-986156 is indicated for use in advanced solid tumor studies.
    BMS-986156
  • HY-W923189
    Neral
    		Inhibitor
    Neral is a monoterpene compound that has anti-inflammatory and anti-cancer properties. Neral can inhibit TNF-α and IL-6, and it also suppresses inflammatory mediators like pro-IL-1β, iNOS, COX-2, and NLRP-3.
    Neral
  • HY-U00142
    A-802715
    		Inhibitor 98.45%
    A802715 is a methylxanthine derivative. A802715 has a TD50 (toxic dose of 50%) of 0.9-1.1 mM.
    A-802715
  • HY-19667
    BMS-561392
    		Inhibitor
    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
  • HY-107909
    Theophylline sodium glycinate
    		Inhibitor
    Theophylline (1,3-Dimethylxanthine) sodium glycinate is a potent phosphodiesterase (PDE) inhibitor, adenosine receptor antagonist, and histone deacetylase (HDAC) activator. Theophylline sodium glycinate inhibits PDE3 activity to relax airway smooth muscle. Theophylline sodium glycinate has anti-inflammatory activity by increase IL-10 and inhibit NF-κB into the nucleus. Theophylline sodium glycinate induces apoptosis. Theophylline sodium glycinate can be used for asthma and chronic obstructive pulmonary disease (COPD) research.
    Theophylline sodium glycinate
  • HY-P99499
    Cetrelimab
    		Activator ≥99.0%
    Cetrelimab (JNJ 63723283; JNJ 3283) is a human IgG4κ mAb targeting PD-1. Cetrelimab binds PD-1 (Kd=1.72 nM, HEK293) to block the interaction of PD-1 with PD-L1 and PD-L2 (IC50s=111.7 ng/mL and 138.6 ng/mL, respectively). Cetrelimab stimulates peripheral T cells, increases IFN-γ, IL-2, TNF-α level and inhibits tumor growth in vivo.
    Cetrelimab
  • 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-P990919
    Gimistotug
    		Inhibitor
    HY-P990919 is an TNFRSF4-targeting IgG1κ type humanized antibody, the recommed isotype control is Human IgG1 kappa, Isotype Control (HY-P99001).
    Gimistotug
  • HY-P99914
    Emfizatamab
    Emfizatamab is an anti-CD19/CD3E/TNFRSF9/PD-L1 monoclonal antibody.
    Emfizatamab
  • HY-P990994
    Emunkitug
    		Inhibitor
    HY-P990994 is an TNFRSF1B-targeting IgG1κ type humanized antibody, the recommed isotype control is Human IgG1 kappa, Isotype Control (HY-P99001).
    Emunkitug
  • HY-P990757
    Ragistomig
    Ragistomig is an anti-TNFRSF9/CD274 IgG1 monoclonal antibody composed of a κ light chain and a variable region with a λ light chain and an IgG1 heavy chain. The overall structure is a dimer composed of two identical IgG1 heavy chains.
    Ragistomig
  • 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
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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