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-P991192
    BI-1808
    		Inhibitor
    BI-1808 is a human IgG1 monoclonal antibody that targets TNFR2by blocking interaction of TNFR2 with ligand TNF-α, confers FcγR-dependent depletion of Treg and mediates expansion of intratumoral CD8+ T cells.
    BI-1808
  • HY-124339
    JNJ525
    		Inhibitor 99.93%
    JNJ525 is a TNFα inhibitor with IC50 values of 1.2 μM and 1.1 μM against TNFR1 and TNFR2, respectively. JNJ525 forms ordered aggregates and induces quaternary structural transition of TNFα, thereby blocking the protein-protein interaction between TNFα and its receptors. The inhibitory activity of JNJ525 is completely lost in the presence of 0.1% Triton X-100.
    JNJ525
  • HY-N0723
    Neomangiferin
    		Inhibitor 99.80%
    Neomangiferin is an orally active natural flavonoid. Neomangiferin partially ameliorates non-alcoholic fatty liver disease (NAFLD) by regulating the expression of genes related to free fatty acid uptake and lipid oxidation. Neomangiferin exerts anti-colitis effects by inhibiting Th17/Treg cell differentiation. Neomangiferin exerts anti-aging and lifespan-extending effects by targeting upregulation of bas-1, which in turn activates the autophagy, IIS and MAPK pathways. Neomangiferin has the potential to prevent aseptic loosening of prostheses after total joint arthroplasty due to its significant anti-inflammatory and osteoclastogenesis-inhibiting effects.
    Neomangiferin
  • HY-76938
    Actarit
    		Inhibitor 99.58%
    Actarit (4-Acetylaminophenylacetic acid) is an orally active Carbonic Anhydrase II (CAII) inhibitor with an IC50 of 422 nM. Actarit shows suppressive effects experimental autoimmune encephalomyelitis in rats. Actarit inhibits the development of type ll collagen (CII)-induced arthritis in mice by suppressing delayed-type hypersensitivity to CII. Actarit can be used for the study of Multiple Sclerosis (MS) and rheumatoid arthritis.
    Actarit
  • HY-P990242
    Anti-Mouse Galectin-9 Antibody (RG9-1)
    		Inhibitor
    Anti-Mouse Galectin-9 Antibody (RG9-1) is an anti-mouse Galectin-9 IgG2b monoclonal antibody. Anti-Mouse Galectin-9 Antibody (RG9-1) promotes inflammatory response by enhancing the secretion of IFN-γ, TNF-α, and IL-6. Anti-Mouse Galectin-9 Antibody (RG9-1) can increase CD8 T cell and Treg frequency. Anti-Mouse Galectin-9 Antibody (RG9-1) reduces graft survival time by increasing CD4+ and CD8+ T cell infiltration. Anti-Mouse Galectin-9 Antibody (RG9-1) can be used for researches on inflammation conditions, cancer and xenotransplantation such as ischemia-reperfusion, colon cancer, breast cancer and leukemia.
    Anti-Mouse Galectin-9 Antibody (RG9-1)
  • HY-W026772
    Fluorene
    		Activator 99.35%
    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
  • HY-P99057
    Varlilumab
    		Inhibitor
    Varlilumab (CDX-1127) is an agonist anti-CD27 monoclonal antibody. Varlilumab can promote T cell expansion and activate the immune response. Varlilumab has anti-tumor activity and can be used in the research of hematological malignancies and solid tumors.
    Varlilumab
  • HY-P990726
    Abiprubart
    		99.00%
    Abiprubart is an anti-CD40 human IgG4 κ monoclonal antibody. Recommend Isotype Controls: Human IgG4 (S228P) kappa, Isotype Control (HY-P99003).
    Abiprubart
  • HY-P99325
    Toralizumab
    		Inhibitor 99.57%
    Toralizumab (IDEC-131) is a humanized monoclonal antibody (mAb) against CD40L (CD154) comprised of human gamma 1 heavy chains and human kappa light chains. Toralizumab binds specifically to human CD40L on T cells, thereby preventing CD40 signaling. Toralizumab is an immunosuppressive agent. Toralizumab can lead to increased thrombosis. Toralizumab can be studied in research for diseases such as multiple sclerosis, systemic lupus erythematosus (SLE), and Crohn’s disease.
    Toralizumab
  • HY-P99119
    Anti-Mouse 4-1BB/CD137 Antibody (3H3)
    		Inhibitor
    Anti-Mouse 4-1BB/CD137 Antibody (3H3) is an anti-mouse 4-1BB/CD137 IgG2a monoclonal antibody. Anti-Mouse 4-1BB/CD137 Antibody (3H3) can effectively activate memory T cells and inhibit tumors by increasing Bcl-xL and granzyme B levels. Anti-Mouse 4-1BB/CD137 Antibody (3H3) can be used for research on cancer such as lymphoma and colon cancer.
    Anti-Mouse 4-1BB/CD137 Antibody (3H3)
  • HY-124750
    NecroX-7
    		Inhibitor 99.69%
    NecroX-7 is a potent free radical scavenger and a HMGB1 (high-mobility group box 1) inhibitor. NecroX-7 can be used as an antidote to acetaminophen toxicity. NecroX-7 exerts a protective effect by preventing the release of HMGB1 in ischemia/reperfusion injury. NecroX-7 inhibits the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. NecroX-7 can be used graft-versus-host disease (GVHD) research.
    NecroX-7
  • HY-N0442
    5-O-Methylvisammioside
    		Inhibitor 99.90%
    5-O-Methylvisammioside (4'-O-β-D-Glucosyl-5-O-methylvisamminol) is an orally active natural chromone glycoside and multiple biological activities. 5-O-Methylvisammioside inhibits ferroptosis by activating the Nrf2/HO-1 signaling axis. 5-O-Methylvisammioside alleviates intestinal barrier damage by inhibiting the ROS/NF-κB/NLRP3 pathway. 5-O-Methylvisammioside exerts a protective effect against acute liver injury by reducing ALT/AST, decreasing inflammatory infiltration, and inhibiting IκB-α phosphorylation and NF-κB nuclear translocation. 5-O-Methylvisammioside blocks the HMGB1/RAGE/MEK/ERK signaling axis to exert anti-tumor and anti-angiogenic effects. 5-O-Methylvisammioside improves depression-like behaviors by inhibiting Src kinase and the NF-κB pathway.
    5-O-Methylvisammioside
  • HY-N6850
    Calenduloside E
    		Inhibitor 99.07%
    Calenduloside E is a pentacyclic triterpenoid saponin that can be extracted from the bark and roots of Aralia ovata, and has anti-inflammatory and anti-apoptotic activities. Calenduloside E alleviates atherosclerosis by regulating macrophage polarization, improves mitochondrial function by regulating the AMPK-SIRT3 pathway, and alleviates acute liver injury. In addition, Calenduloside E promotes the interaction between L-type calcium channels and Bcl-2 related apoptosis genes, inhibits calcium overload, and alleviates myocardial ischemia/reperfusion injury. Calenduloside E also improves non-alcoholic fatty liver disease by regulating heat shock-dependent pathways, and inhibits ROS mediated JAK1-STAT3 pathways to reduce cellular inflammatory responses.
    Calenduloside E
  • HY-113763
    L524-0366
    		Inhibitor 99.95%
    L524-0366 is a specific, dose-dependent TWEAK-Fn14 inhibitor. L524-0366 specifically binds to the Fn14 surface with a KD of 7.12 μM, competitively inhibiting the binding of Fn14 to TWEAK (inhibition rate reaching 16%). L524-0366 inhibits TWEAK-induced glioma cell migration without potential cytotoxic effects.
    L524-0366
  • HY-100755
    KR-33493
    		Inhibitor 99.94%
    KR-33493 is a potent inhibitor of Fas-mediated cell death (FAF1).
    KR-33493
  • HY-W1000105
    Geranial
    		99.51%
    Geranial is an aromatic compound. It can be isolated from the fruits of Litsea cubeba Lour and the rhizomes of ginger (Zingiber officinale). Geranial inhibits LPS-induced phosphorylation of ERK1/2, JNK1/3 and IκB in macrophages. It suppresses the secretion of IL-1β, TNF-α and IL-6, as well as the expression of pro-IL-1β, iNOS and COX-2. Geranial increases ROS. It can be used in the research of inflammatory diseases.
    Geranial
  • HY-P991440
    AMG-966
    		Inhibitor
    AMG-966 is a human bispecific antibody (bsAb) targeting TNFSF15/TL1A & TNFα. AMG 966 restores the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of anti-drug antibodies (ADA). AMG 966 can be used in research on Crohn's disease and ulcerative colitis. Recommended isotype control: Human IgG1 kappa, Isotype Control (HY-P99001).
    AMG-966
  • HY-122822
    GSK699
    		Inhibitor 98.80%
    GSK699 is a KAT2A/B/PCAF/GCN5 PROTAC degrader. GSK699 induces proteasome-dependent degradation of KAT2A, KAT2B, PCAF and GCN5, regulates the histone acetyltransferase activity of the SAGA complex, and reduces the level of histone H3K9ac. GSK699 inhibits the growth of neuroblastoma, acute myeloid leukemia and small cell lung cancer cells. GSK699 reduces the production of inflammatory cytokines and chemokines, and impairs LPS-stimulated immune cell responses. GSK699 is applicable to research related to acute myeloid leukemia, small cell lung cancer, neuroblastoma and inflammatory diseases.
    GSK699
  • HY-P990860
    Anti-CD40 Antibody (G28.5)
    		Inhibitor
    Anti-CD40 Antibody (G28.5) is a kind of mouse IgG1 κ chimeric agonistic antibody, targeting to human CD40. Anti-CD40 Antibody (G28.5) can activate CD40 signaling and promote anti-tumor T cell responses. Anti-CD40 Antibody (G28.5) can be used for the research of cancer, such as endometrial cancer.
    Anti-CD40 Antibody (G28.5)
  • HY-19929
    Tanimilast
    		Antagonist 99.71%
    Tanimilast (CHF-6001) is an orally active and selective phosphodiesterase 4 inhibitor (IC50=0.026 nM) with robust anti-inflammatory activity and suitable for topical pulmonary administration. Tanimilast increases cellular cAMP levels, and inhibits NF-κB signaling pathway. Tanimilast is used for the research of obstructive lung diseases.
    Tanimilast
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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