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-125025
    SMI 6860766
    		Inhibitor
    SMI 6860766, a small molecule inhibitor of CD40-TRAF6 interaction, improves glucose tolerance, reduces immune cell accumulation in adipose tissue, and reduces AT inflammation.
    SMI 6860766
  • HY-P99425
    Afelimomab
    		99.34%
    Afelimomab (MAK 195F) is an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment. Afelimomab can be used for the research of sepsis.
    Afelimomab
  • HY-164894
    ABBV-3373
    		Inhibitor 98.78%
    ABBV-3373 is an anti-TNF antibody drug conjugate (ADC). ABBV-3373 is composed of the humanized antibody Adalimumab (HY-P9908) conjugated with a glucocorticoid receptor modulator (HY-148436). ABBV-3373 can be used in the study of rheumatoid arthritis.
    ABBV-3373
  • HY-114592
    M199
    		Activator 98.55%
    M199 is a potent TLR3/TLR9 signaling inhibitor. M199 induces secretion of IL-6, IL-8 and TNFα in human PBMCs. M199 is used as a selective inducer of the immune response.
    M199
  • 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-P99663
    Inezetamab
    		Inhibitor 99.77%
    Inezetamab is a bispecific anti-CD40 and anti-MSLN IgG1 monoclonal antibody.
    Inezetamab
  • HY-N1195
    Sugiol
    		Inhibitor 99.88%
    Sugiol is an abietane diterpenoid, can be isolated from Calocedrus formosana bark. Sugiol has anti-inflammatory activity, could effectively reduce intracellular reactive oxygen species (ROS) production in lipopolysaccharide (LPS)-stimulated macrophages.
    Sugiol
  • HY-N1965
    Gaultherin
    		Inhibitor 99.44%
    Gaultherin is an orally active non-steroidal anti-inflammatory agent. Gaultherin selectively inhibits NF-κB, MAPK, COX-2 (IC50 = 0.35 mg/mL), LOX (IC50 = 0.56 mg/mL) and HYAL (IC50 = 28.58 μg/mL) to exert anti-inflammatory, antipyretic and analgesic effects. Gaultherin exhibits modest direct antioxidant capacity, greater in cell-based models. Gaultherin does not affect COX-1 so that avoids the common gastrointestinal side effects of Aspirin (HY-14654).
    Gaultherin
  • HY-P9980A
    Belantamab (FUT8-KO)
    		98.10%
    Belantamab (FUT8-KO) is an anti-BCMA (TNFRSF17) monoclonal antibody expressed by CHO cells with the fucosyltransferase 8 gene (FUT8) knocked out. Fucose deficiency enhances the ADCC effect of the antibody. Belantamab (FUT8-KO) can be used to synthesize antibody-active molecule conjugate (ADC), Belantamab mafodotin.
    Belantamab (FUT8-KO)
  • 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-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-172458
    Z-3578
    		Inhibitor 98.72%
    Z-3578 is a small-molecule antagonist targeting MrgX2 (Mas-related G protein-coupled receptor X2) with significant anti-pseudoallergic activity and a KD value of 729 nM. Z-3578 effectively inhibits mast cell degranulation induced by substance P (SP) and C48/80, suppressing the release of β-hexosaminidase with IC50 values of 4.90 µM and 6.18 µM, respectively. It also markedly reduces the release of histamine and TNF-α, along with intracellular calcium flux. In a murine pseudoallergy model, Z-3578 significantly alleviates paw swelling and dye extravasation and lowers serum histamine levels, indicating potent in vivo anti-allergic effects. Z-3578 holds promise as a lead compound for the treatment of allergic diseases, especially pseudoallergic reactions.
    Z-3578
  • 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-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-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-P990994
    Emunkitug
    		Inhibitor 99.09%
    HY-P990994 is an TNFRSF1B-targeting IgG1κ type humanized antibody, the recommed isotype control is Human IgG1 kappa, Isotype Control (HY-P99001).
    Emunkitug
  • 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-P99057A
    Varlilumab (anti-CD27)
    		Inhibitor 99.68%
    Varlilumab (CDX-1127) (anti-CD27) is an agonist anti-CD27 monoclonal antibody. Varlilumab (anti-CD27) can promote T cell expansion and activate the immune response. Varlilumab (anti-CD27) has anti-tumor activity and can be used in the research of hematological malignancies and solid tumors.
    Varlilumab (anti-CD27)
  • HY-P99704
    Licaminlimab
    		Inhibitor
    Licaminlimab (OCS-02) is a single-chain anti-TNF alpha antibody fragment. TNF alpha is an inflammatory cytokine produced by macrophages and monocytes during inflammation.
    Licaminlimab
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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