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-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-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
  • HY-121892
    (Z)-KC02
    (Z)-KC02 is an inhibitor of ABHD16A, the phosphatidylserine (PS) lipase that produces lyso-PS. Lysophosphatidylserine (lyso-PS) is a signaling lipid that regulates immune and neurological processes. It is associated with several neurological disorders such as retinitis pigmentosa and cataracts (PHARC). (Z)-KC02 depletes lyso-PS in lymphoblasts from PHARC subjects. (Z)-KC02 also reduces lyso-PS and lipopolysaccharide-induced cytokine production in macrophages and modulates lyso-PS metabolism in vivo.
    (Z)-KC02
  • HY-N8884
    Coelonin
    		Inhibitor ≥98.0%
    Coelonin is a dihydrophenanthrene with anti-inflammation activity. Coelonin inhibits LPS-induced PTEN phosphorylation. Coelonin inhibits NF-κB activation and p27Kip1 degradation by regulating the PI3K/AKT pathway negatively. Coelonin can inhibit IκBα phosphorylation and degradation and increases the expression of IκBα protein.
    Coelonin
  • HY-100573S
    Necrosulfonamide-d4
    		Inhibitor 99.26%
    Necrosulfonamide-d4 is the deuterium labeled Necrosulfonamide (HY-100573). Necrosulfonamide is a MLKL and Gasdermin D (GSDMD) inhibitor, capable of separately inhibiting necroptosis and pyroptosis of cells. Necrosulfonamide does not affect the activation of upstream signals, but specifically inhibits the downstream executor oligomerization step. Necrosulfonamide reduces the expression of the key kinases NLRP3 and caspase-1 involved in necroptosis and pyroptosis, activate the Nrf2 pathway and the downstream antioxidant enzymes, and also downregulates a variety of inflammatory factors. Necrosulfonamide plays significant roles in various diseases such as neurodegenerative diseases (such as Parkinson’s disease), tissue damage and ischemia-reperfusion injury, inflammatory bowel disease, osteoarthritis and fracture repair, and hair loss by regulating two important programmed necrosis pathways.
    Necrosulfonamide-d<sub>4</sub>
  • HY-N10913
    Chloranthalactone B
    		Inhibitor
    Chloranthalactone B, a lindenane-type sesquiterpenoid, is a nature product that could be isolated from Chinese medicinal herb Sarcandra glabra. Chloranthalactone B inhibits the production of inflammatory mediators by inhibiting the AP-1 and p38 MAPK pathways.
    Chloranthalactone B
  • HY-B0026
    Ceftiofur hydrochloride
    		Inhibitor 98.43%
    Ceftiofur hydrochloride is a cell wall synthesis inhibitor that targets bacterial penicillin-binding proteins (PBPs) and has anti-inflammatory effects in endotoxemia. Ceftiofur hydrochloride exerts bactericidal effects by inhibiting the synthesis of bacterial cell wall peptidoglycan, leading to bacterial cell lysis. Ceftiofur hydrochloride 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 hydrochloride
  • HY-P99563
    Tibulizumab
    		Inhibitor 98.86%
    Tibulizumab (LY 3090106) is a tetravalent bispecific monoclonal antibody targeting B-cell activating factor (BAFF) and IL-17A with Kd values of 60 pM and 14 pM, respectively. Tibulizumab can be used for autoimmune disease research.
    Tibulizumab
  • HY-P99825
    Relfovetmab
    		Inhibitor 99.88%
    Relfovetmab is an anti-NGF monoclonal antibody (mAb).
    Relfovetmab
  • HY-P99914
    Emfizatamab
    Emfizatamab is an anti-CD19/CD3E/TNFRSF9/PD-L1 monoclonal antibody.
    Emfizatamab
  • HY-P3149B
    LEESGGGLVQPGGSMK acetate
    		99.01%
    LEESGGGLVQPGGSMK acetate, a proteolysis peptide, is a component of Infliximab. LEESGGGLVQPGGSMK acetate can be used for quantitative analysis of Infliximab. Infliximab is a chimeric monoclonal IgG1 antibody that specifically binds to TNF-α.
    LEESGGGLVQPGGSMK acetate
  • HY-147086
    CAY10789
    		Inhibitor 99.84%
    CAY10789 is a potent CysLT1R (cysteinyl leukotriene receptor 1) antagonist (IC50=2.80 μM) and GPBAR1 (G-protein-coupled bile acid receptor 1) agonist (EC50=3 μM). CAY10789 significantly reduces the adhesion of U937 cells to HAEC, reduces the expression of TNF-α. CAY10789 shows very promising metabolic stability and excellent pharmacokinetics. CAY10789 can be used for the research of colitis, metabolic syndromes, and other GPBAR1/CysLT1R-related diseases.
    CAY10789
  • HY-100376
    CPI-1189
    		Inhibitor 99.82%
    CPI-1189 is an orally active TNF-α release inhibitor. CPI-1189 inhibits phosphorylation of p38. CPI-1189 can inhibit apoptosis. CPI-1189 can be used in the study of HIV and neurological diseases.
    CPI-1189
  • HY-W010201R
    Citronellol (Standard)
    		Modulator
    Citronellol (Standard) is the analytical standard of Citronellol. Citronellol (Standard) is an orally active inducer of apoptosis. Citronellol (Standard) can prevent oxidative stress, mitochondrial dysfunction, and apoptosis in the SH-SY5Y cell Parkinson's disease model induced by 6-OHDA by regulating the ROS-NO, MAPK/ERK, and PI3K/Akt signaling pathways. Citronellol (Standard) can induce necroptosis in human lung cancer cells through the TNF-α pathway and accumulation of ROS. Citronellol (Standard) can reduce the levels of LC-3 and p62 to regulate the autophagy pathway, inhibit oxidative stress and neuroinflammation, and thus have neuroprotective effects on Parkinson's rats. Citronellol (Standard) exhibits anti-fungal activity against Trichophyton rubrum by inhibiting ergosterol synthesis.
    Citronellol (Standard)
  • HY-P99775
    Placulumab
    		Inhibitor
    Placulumab (ART621) is an anti-TNF α monoclonal antibody. Placulumab has anti-inflammatory activity and has potential applications in inflammatory diseases such as arthritis.
    Placulumab
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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