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-139066
    Punicic acid
    		Inhibitor 98.5%
    Punicic acid is a bioactive compound of pomegranate seed oil. Punicic acid is an isomer of conjugated α-linolenic acid and ω-5 polyunsaturated fatty acids. Punicic acid has anti-inflammatory and antioxidant activities and can inhibit the expression of inflammatory mediators such as tumor necrosis factor α (TNF-α). Punicic acid can also reduce the formation of β-amyloid deposits and hyperphosphorylation of tau by increasing the expression of GLUT4 protein and inhibiting the overactivation of calpain, and is used to prevent and treat neurodegenerative diseases. In addition, punicic acid also has breast cancer inhibitor properties that depend on lipid peroxidation and PKC pathways.
    Punicic acid
  • HY-B2162D
    Chondroitin sulfate (from chicken)
    		Inhibitor 99.61%
    Chondroitin sulfate (from chicken) (Chondroitin polysulfate (from chicken)) is an orally active, sulfated linear polysaccharide extracted from chickens, which belongs to glycosaminoglycans. Chondroitin sulfate (from chicken) reduces the phosphorylation levels of ERK1/2 and p38MAPK, inhibits the expression of inflammatory cytokines and MMP, and downregulates the levels of IL-1β, IL-6, TNF-α and PGE2. Chondroitin sulfate (from chicken) improves motor function, protects cartilage tissue, reverses chondrocyte aggregation, and regulates the structure of intestinal flora. Chondroitin sulfate (from chicken) can be used in research related to osteoarthritis.
    Chondroitin sulfate (from chicken)
  • HY-N0594
    Deacetylasperulosidic Acid
    		Inhibitor 99.44%
    Deacetylasperulosidic Acid is an orally active antioxidant. Deacetylasperulosidic Acid exerts a definite in vivo antioxidant effect and alleviates oxidative stress injury by enhancing SOD activity. In atopic dermatitis models, Deacetylasperulosidic Acid corrects Th2-skewed immune imbalance and reduces allergy-related factors; in immunosuppression models, it activates cellular immunity, enhances NK cell activity and IL-2 production. Deacetylasperulosidic Acid can be used in the research of atopic dermatitis.
    Deacetylasperulosidic Acid
  • HY-N2086
    Ethyl palmitate
    		Inhibitor 99.09%
    Ethyl palmitate (Ethyl hexadecanoate) is a CHIKV virus inhibitor with an EC50 value of 0.0068 μM. Ethyl palmitate can reduce levels of TNF-α, IL-6, and NF-κB in endotoxemic rats, showing anti-inflammatory activity.
    Ethyl palmitate
  • HY-P990710
    Acimtamig
    		99.9%
    Acimtamig (AFM13) is a CD30/CD16A bispecific innate cell engager. Acimtamig binds to the CD16A expressed on natural killer (NK) cells and binds to CD30 on CD30-expressing tumor cells, thereby selectively cross-linking tumor and NK cells. Acimtamig can be used for the study of eripheral T-cell lymphoma (PTCL).
    Acimtamig
  • HY-P10086
    TREM-1 inhibitory peptide GF9
    		Inhibitor 99.41%
    TREM-1 inhibitory peptide GF9 (Human TREM-1 (213-221)) is a TREM-1 inhibitor. TREM-1 inhibitory peptide GF9 blocks the TREM-1 signaling pathway via a ligand-independent mechanism, spontaneously inserts into the cell membrane to dissociate TREM-1 from DAP-12, and functions through the Signaling Chain Homooligomerization (SCHOOL) model. TREM-1 inhibitory peptide GF9 reduces the levels of TNFα, IL-1β, IL-6, and M-CSF. TREM-1 inhibitory peptide GF9 inhibits tumor growth, prolongs the survival of mice with pancreatic cancer models, ameliorates collagen-induced arthritis, and exerts protective effects on bone and cartilage simultaneously. TREM-1 inhibitory peptide GF9 can be used in research related to arthritis, pancreatic cancer, retinopathy, alcoholic liver disease, and liver cancer.
    TREM-1 inhibitory peptide GF9
  • HY-P2310
    Defensin HNP-1 human
    		Activator 98.12%
    Defensin HNP-1 human is a type of human neutrophil peptide (HNPs). Defensin HNP-1 human possesses immunomodulatory functions and can delay the apoptosis of neutrophils. Defensin HNP-1 human inhibits DNA/RNA/protein synthesis and interferes with metabolic pathways, thus exhibiting broad antibacterial activity. Defensin HNP-1 human has direct inactivation effects on HIV, HSV-1, HSV-2, CMV, influenza virus, etc. Defensin HNP-1 human has antileishmanial activity. Defensin HNP-1 human is involved in endothelial cell dysfunction during the early development of atherosclerosis.
    Defensin HNP-1 human
  • HY-139481
    TL-895
    		Inhibitor 99.86%
    TL-895 is a potent, orally active, ATP-competitive, and highly selective irreversible BTK inhibitor. TL-895 is active against recombinant BTK (average IC50: 1.5 nM) and inhibits only three additional kinases BLK, BMX (IC50 = 1.6 nM) and TXK with IC50 within tenfold of BTK activity. TL-895 inhibits BTK auto-phosphorylation at the Y223 phosphorylation site (IC50: 1-10 nM). The TL-895 effectively inhibits the production of inflammatory factors such as IL-8, IL-1β, MCP-1 and TNF-α by monocytes or macrophages, and reduces the chemotactic migration of MF cells towards SDF-1. TL-895 is used be for studies of chronic lymphocytic leukemia (CLL), myelofibrosis (MF), and B-cell malignancies.
    TL-895
  • HY-P99390
    Tepoditamab
    		Inducer ≥99%
    Tepoditamab (MCLA-117) is a full-length human IgG1 bispecific monoclonal antibody that binds to CLEC12A of myeloid cells and CD3 of cytotoxic T cells. Among others, CLEC12A is a myeloid differentiation antigen. Tepoditamab kills AML leukaemia mother cells and AML leukaemia stem cells, induces T cell-mediated proliferative lysis of AML cells. Tepoditamab induces upto 30-fold T-cell expansion. Tepoditamab results in moderate to strong cytokine (IFNγ, IL-6, IL-8, IL-10, and TNFα) and IFNγ release in human whole blood and PBMC, respectively. Tepoditamab can be used in acute myeloid leukaemia (AML) research.
    Tepoditamab
  • HY-P99149
    Anti-Mouse TNFR2 Antibody (TR75-54.7)
    		Inhibitor 98.864%
    Anti-Mouse TNFR2 Antibody (TR75-54.7) is an anti-mouse TNFR2 IgG monoclonal antibody. Anti-Mouse TNFR2 Antibody (TR75-54.7) can reduce white blood cell count (WBC) and decrease the expression of some pro-inflammatory cytokines such as CCL2 and CXCL5. Anti-Mouse TNFR2 Antibody (TR75-54.7) can be used for researches on inflammation conditions and cancer such as breast cancer.
    Anti-Mouse TNFR2 Antibody (TR75-54.7)
  • HY-P990742
    Givastomig
    		Inhibitor 98.556%
    Givastomig (ABL111, TJ033721) is a bispecific antibody (BsAb) inhibitor. Givastomig can specifically binds to Claudin18.2 (CLDN 18.2) on the surface of cancer cells and 4-1BB (CD137, TNFRSF9) on the surface of activated T cells and natural killer (NK) cells. Givastomig is engineered to contain a single Fc-domain mutation (asparagine to alanine) to eliminate Fc-effector function. Givastomig-bound cell lines expressing a range of CLDN18.2 levels with high affinity and induced 4-1BB activation only in the context of CLDN18.2 binding. Givastomig can be used for the study of colon carcinoma.
    Givastomig
  • HY-N2255
    Crebanine
    		Inhibitor 99.83%
    Crebanine is an isoquinoline-like alkaloid that can be derived from Stephania. Crebanine is an antagonist of the α7-nAChR with an IC50 of 19.1 μM. Crebanine suppresses the proliferation, migration, and invasion of cancer cells, triggers reactive oxygen species (ROS) burst, and promotes apoptosis. Crebanine inhibits the AKT/FoxO3a, NF-κB and MAPK signaling pathways. Crebanine attenuates NOX2 hyperactivation, exhibits antioxidant properties by reducing reactive oxygen species and peroxidation in microglia cells. Crebanine inhibits voltage-dependent Na+ current in guinea-pig ventricular myocytes. Crebanine has high inhibitory activity against gram-positive animal pathogenic bacteria. Crebanine ameliorates ischemia-reperfusion brain damage in middle cerebral artery occlusion and reperfusion (MCAO/R) rats. Crebanine significantly improves Scopolamine (HY-N0296)-induced cognitive deficits in ICR mice. Crebanine can be used for the study of hepatocellular carcinoma (HCC), cerebral ischemia and Alzheimer's disease.
    Crebanine
  • HY-20070
    BMS-566394
    		Inhibitor 99.95%
    BMS-566394 is a selective, orally active TACE (ADAM17) inhibitor. BMS-566394 inhibits LPS-induced TNF-α production in whole blood. BMS-566394 selectively inhibits TACE activity.
    BMS-566394
  • HY-B0898
    Ceftiofur sodium
    		Inhibitor 98.02%
    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
  • HY-N4124
    Poricoic acid B
    		Inhibitor 98.60%
    Poricoic acid B is a triterpenoid compound that can be isolated from Poria cocos. Poricoic acid B inhibits intracellular lipid accumulation and reduces the levels of hepatocyte injury markers. Poricoic acid B inhibits the production of NO, TNF-α, IL-1β and IL-6, thereby exerting anti-inflammatory activity. Poricoic acid B can be used in the research of metabolic dysfunction-associated fatty liver disease and inflammatory diseases[3].
    Poricoic acid B
  • HY-P991193
    NGM-438
    		Activator 99.74%
    NGM-438 is a humanized monoclonal antibody antagonist of LAIR1, with a Ka of 0.26 nM for human LAIR1 and 4.28 nM for cynomolgus monkey LAIR1. NGM-438 blocks the binding of LAIR1 to its Collagen ligand and antagonizes the Collagen-induced LAIR1 signaling pathway. NGM-438 reverses FcγR signaling inhibition in myeloid cells, induces dendritic cells to secrete TNFα, promotes T cell proliferation, and triggers myeloid inflammation and allogeneic T cell responses. NGM-438 sensitizes refractory mouse lung cancer to PD-1 blockade, increases the content of intratumoral CD8+ T cells and the expression of inflammatory genes. NGM-438 is applicable to research related to solid tumors, refractory solid tumors and non-small cell lung cancer.
    NGM-438
  • HY-P991155
    Ramantamig
    		Inhibitor
    Ramantamig (JNJ-79635322) is a humanized monoclonal antibody targeting human CD3ε, GPRC5D, and TNFRSF17 (BCMA). Ramantamig binds to BCMA and GPRC5D on multiple myeloma cells, binds to CD3ε on T cells, forms immunological synapses, and enables T-cell-mediated cytotoxicity. Ramantamig activates T cells concomitantly with inducing myeloma cell cytotoxicity, with no nonspecific T-cell activation in the absence of target myeloma cells. Ramantamig carries mutations to reduce interaction with Fc receptors and disrupt protein A binding of monomeric and homodimerized chains. Ramantamig can be used for the research of multiple myeloma.
    Ramantamig
  • HY-107390A
    AX-024 hydrochloride
    		Inhibitor 99.23%
    AX-024 hydrochloride is an orally available, first-in-class inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 ~1 nM. AX-024 hydrochloride modulates cell signaling by targeting SH3 domains. AX-024 hydrochloride has low-acute toxicity and high potency and selectivity, and strongly inhibit the production of IL-6, TNF-α, IFN-γ, IL-10 and IL-17A.
    AX-024 hydrochloride
  • HY-P99167
    Lucatumumab
    		Inhibitor ≥99.0%
    Lucatumumab (HCD122) is a fully human anti-CD40 antagonist monoclonal antibody, which blocks CD40/CD40L-mediated signaling. Lucatumumab efficiently mediates antibody-dependent cell-mediated cytotoxicity (ADCC) and clearance of tumor cells, can be used for refractory lymphomas, CLL and multiple myeloma research.
    Lucatumumab
  • HY-P99701
    Letolizumab
    		Inhibitor 98.32%
    Letolizumab (BMS-986004) is a monoclonal antibody targeting CD40L, which is produced to express mutant IgG1 lacking effector function, including Fc binding and complement fixation. Letolizumab reduces rejection, thromboembolism and prolongs the survival time.
    Letolizumab
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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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