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-N8593
    Undecane
    		Inhibitor 99.66%
    Undecane is a potent cAMP agonist with anti-allergic and anti-inflammatory activities. Undecane inhibits degranulation and the secretion of histamine and TNF-α. Undecane reverses the increased levels of p38 phosphorylation, NF-κB transcriptional activity and target cytokine/chemokine genes, including thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC) and interleukin-8 (IL-8). Undecane can be used for the study of skin inflammatory disorders, such as atopic dermatitis.
    Undecane
  • HY-138793
    2-(2,6-Dioxopiperidin-3-yl)phthalimidine
    		Inhibitor 98.08%
    2-(2,6-Dioxopiperidin-3-yl)phthalimidine (EM-12), a teratogenic Thalidomide analogue, is more active than Thalidomide and is much more stable for hydrolysis. 2-(2,6-Dioxopiperidin-3-yl)phthalimidine enhances 1,2-dimethylhydrazine-induction of rat colon adenocarcinomas.
    2-(2,6-Dioxopiperidin-3-yl)phthalimidine
  • HY-P990124
    Anti-Mouse GITR Antibody (DTA-1)
    		Agonist 98.47%
    Anti-Mouse GITR Antibody (DTA-1) is a rat derived IgG2b monoclonal agonist antibody targeting mouse GITR. Anti-Mouse GITR Antibody (DTA-1) can activate T cells and B cells to enhance immune response. Anti-Mouse GITR Antibody (DTA-1) selectively enhances Th2 cell effector function through GITR signaling. Anti-Mouse GITR Antibody (DTA-1) may exacerbate allergic reactions. Anti-Mouse GITR Antibody (DTA-1) can be used for researches on cancer and allergic conditions such as colon cancer and allergic asthma. The recommed isotype control of Anti-Mouse GITR Antibody (DTA-1) is Rat IgG2b kappa, Isotype Control (HY-P990682).
    Anti-Mouse GITR Antibody (DTA-1)
  • HY-N0854
    Alisol F
    		Inhibitor 99.89%
    Alisol F is a protostane-type triterpenoid with anti-inflammatory and anti-hepatitis B virus activities. Alisol F inhibits LPS (HY-D1056)-induced phosphorylation of ERK, JNK, p38, STAT3 and NF-κB (p65), suppresses the production of NO, IL-6, TNF-α and IL-1β, and also downregulates the levels of iNOS and COX-2. Alisol F reduces the serum alanine aminotransferase and aspartate aminotransferase levels in mice with acute liver injury and ameliorates their liver pathological damage.
    Alisol F
  • HY-100573A
    (E/Z)-Necrosulfonamide
    		Inhibitor 98.03%
    (E/Z)-Necrosulfonamide is a racemic compound of 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.
    (E/Z)-Necrosulfonamide
  • HY-B0113S
    Omeprazole-d3
    		98.99%
    Omeprazole-d3 (H 16868-d3) is deuterium labeled Omeprazole. Omeprazole (H 16868) is an orally active H+,K+-ATPase inhibitor and a proton pump inhibitor. Omeprazole competitively inhibits CYP2C19, CYP3A4, and CYP2C9 activity. Omeprazole inhibits gastric acid secretion and can be used for acid-related gastrointestinal disorders. Omeprazole inhibits pancreatic cancer cell proliferation, induces apoptosis, autophagosome accumulation (elevated LC3-I and LC3-II levels), oxidative stress, and cytogenetic imbalance, modulates lysosomal transport, reduces inflammatory cytokines. Omeprazole alters small intestinal morphology and magnesium absorption, and induces gastric mucosa morphologic changes. Omeprazole aslo has neuroprotective and antibacterial effects.
    Omeprazole-d<sub>3</sub>
  • 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-P990040
    Exlinkibart
    		Inhibitor 99.66%
    Exlinkibart (LVGN-6051) targets TNFRSF9 and is an IgG1κ antibody humanized through complementarity-determining region (CDR) grafting technology.
    Exlinkibart
  • HY-P990018
    Boserolimab
    		Inhibitor 99.00%
    Boserolimab (MK-5890) is a humanized agonist monoclonal antibody that binds to CD27 to provide a costimulatory signal that enhances T-cell–mediated responses.
    Boserolimab
  • HY-P990067
    Evunzekibart
    		Inhibitor
    Evunzekibart (ATOR-1017) is an Fc-γ receptor conditional 4-1BB agonist and IgG4-type antibody. Evunzekibart can be used as monotherapy or in combination with anti-PD1 to exert anticancer activity.
    Evunzekibart
  • 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-P99830
    Conbercept
    		Inhibitor 98.42%
    Conbercept (KH902) is a recombinant fusion protein composed of VEGFR-1 (second domain) and VEGFR-2 (third and fourth domains) regions fused to human IgG1 Fc. Conbercept is a VEGF inhibitor (IC50 = 8.8 pM) and is a soluble receptor decoy that blocks all isoforms of VEGF-A (Kd = 0.5 pM), VEGF-B (Kd = 8 pM), VEGF-C, and PlGF (Kd = 5 pM). Conbercept has anti-inflammatory effects, can lower the levels of VEGF, TNF-α and IL-6, and reduce the infiltration of inflammatory cells. Conbercept decreases tumor growth in several oncology studies. Conbercept can be used for various eye diseases such as polypoidal choroidal vasculopathy (PCV), diabetic macular edema (DME) and pathologic myopia choroidal neovascularization (pmCNV).
    Conbercept
  • HY-122663
    (Rac)-BIO8898
    		Inhibitor 98.03%
    (Rac)-BIO8898 is a CD40-CD154 co-stimulatory interaction inhibitor. (Rac)-BIO8898 inhibits CD154 binding to CD40-Ig with an IC50 of 25 μM.
    (Rac)-BIO8898
  • HY-P990657
    RG-7212 (RO5458640)
    		Inhibitor 99.62%
    RG-7212 (RO5458640) is a human-derived antibody expressed in CHO cells, targeting TNFSF12/TWEAK. RG-7212 (RO5458640) has a huIgG1 type heavy chain and a huκ type light chain, with a predicted molecular weight (MW) of 146.02 kDa. The isotype control for RG-7212 (RO5458640) can be referenced as Human IgG1 kappa, Isotype Control (HY-P99001).
    RG-7212 (RO5458640)
  • HY-106359A
    Delmitide acetate
    		Inhibitor 99.22%
    Delmitide (RDP58) acetate is an orally active d-isomer decapeptide with potent anti-inflammatory activity. Delmitide acetate inhibits production of TNF-α, IFN-γ, and interleukin (IL)-12, and up-regulates heme oxygenase 1 activity. Delmitide acetate can be used for the research of ulcerative colitis.
    Delmitide acetate
  • HY-177338
    STING agonist-45
    		Agonist 99.10%
    STING agonist-45 is a selective STING agonist (EC50 = 0.28 μM). STING agonist-45 activates the innate immune response through the cGAS-STING pathway, upregulating key markers such as p-TBK1 and IRF3. STING agonist-45 exhibits robust STING activation in human peripheral blood mononuclear cells (PBMCs), inducing the production of type I interferons (such as IFN-β) and downstream cytokines (such as TNF-α and IL-6). STING agonist-45 enhances anti-tumor immunity, inhibits tumor growth, and increases CD8+ T cell infiltration in mouse models. STING agonist-45 is promising for the study of STING-related diseases.
    STING agonist-45
  • HY-P99914
    Emfizatamab
    Emfizatamab (GNC-038) is a monoclonal antibody against CD19/CD3E/TNFRSF9/PD-L1. Emfizatamab exhibits antitumor activity, being capable of activating CD3 and 4-1BB signals on T cells, as well as targeting the high expression of CD19 or PD-L1 on tumor cells. Emfizatamab functions as a CD19-specific T cell engager by mediating direct antitumor activity. Emfizatamab can also overcome the inhibition of T cells by PD-L1. Emfizatamab can be used in the research of tumors such as R/R non-Hodgkin lymphoma or acute lymphoblastic leukemia.
    Emfizatamab
  • HY-W047187
    Lavandoside
    		Inhibitor 99.98%
    Lavandoside is an ABTS?+ free radical scavenger and a moderate inhibitor of xanthine oxidase (XO), with an IC50 of 71.6 μM for inhibiting NO production in LPS-induced macrophages. Lavandoside exerts its antioxidant and potential anti-inflammatory effects by directly scavenging free radicals and inhibiting XO activity, a mechanism related to the hydroxyl groups in its molecular structure. Lavandoside can be isolated from lavender and can be used in the development of natural antioxidants and in research on oxidative stress-related diseases and inflammation-related diseases.
    Lavandoside
  • HY-107101
    (5R)-5-Hydroxytriptolide
    		Inhibitor 99.67%
    (5R)-5-Hydroxytriptolide is an extracted compound from Tripterygium, and shows lower cell cytotoxicity and higher immunosuppressive activity. (5R)-5-Hydroxytriptolide can be used for study of rheumatoid arthritis.
    (5R)-5-Hydroxytriptolide
  • HY-114095
    BML-280
    		Inhibitor 99.64%
    BML-280 (VU0285655-1) is a potent and selective phospholipase D2 (PLD2) inhibitor. BML-280 has the ability to prevent caspase-3 cleavage and reduction in cell viability induced by high glucose. BML-280 can be used for rheumatoid arthritis research.
    BML-280
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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