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-N3364
    Lucidone
    		Inhibitor
    Lucidone, an anti-inflammatory agent that can be isolated from the fruit of Lindera erythrocarpa Makino. Lucidone inhibits LPS-induced NO and PGE2 production in RAW 264.7 mouse macrophages. Lucidone also decreases TNF-α secretion, iNOS and COX-2 expression. Lucidone prevents NF-κB translocation and inhibits JNK and p38MAPK signals. Lucidone also has inhibitory activity against Dengue virus (DENV) (EC50=25 μM).
    Lucidone
  • HY-172977
    FGA139
    		Inhibitor
    FGA139 is a cysteine proteases inhibitor with IC50 values of 4.98/3.14 μM for cathepsin B/L. FGA139 reduces LPS-induced NO production in RAW264.7 cells and tumor necrosis factor (TNFα) levels in microglia, and has anti-oxidative stress and anti-inflammatory activities. FGA139 promotes the secretion of neuroprotective metabolites purine and linoleic acid by LPS-stimulated microglia. FGA139 can be used in neuroinflammatory diseases research.
    FGA139
  • HY-160435
    TNF-α-IN-14
    		Inhibitor
    TNF-α-IN-14 is a potent and selective TNFα inhibitor with an IC50 value of 1.1 µM. TNF-α-IN-14 shows antiinflammatory properties (WO2001072735A2; compound 12).
    TNF-α-IN-14
  • HY-179429
    NLRP3-IN-85
    		Inhibitor
    NLRP3-IN-85 (compound 5d) is a potent NLRP3 inhibitor that targets mitochondria in a ΔΨm-independent manner. NLRP3-IN-85 protects mitochondria from oxidative stress and inflammation damage and suppresses key inflammatory factors (NO, TNF-α, IL-6). NLRP3-IN-85 relives acute lung injury in mice and inhibits paw edema in rats. NLRP3-IN-85 can be used for acute lung injury (ALI) research.
    NLRP3-IN-85
  • HY-151188
    DHU-Se1
    		Inhibitor
    DHU-Se1 is a potent anti-inflammatory agent. DHU-Se1 can stimulate macrophages to release the reactive selenium compound and reduce the expression of cellular inflammatory factors (eg: iNOS and TNF-α). DHU-Se1 alleviate the process of inflammation by blocking the polarization of macrophages from M0 to M1.
    DHU-Se1
  • HY-181685
    LAGi-DEL
    		Inhibitor
    LAGi-DEL is a LAG-3 inhibitor, with Kd values of 97.33 nM and 271 nM in surface plasmon resonance (SPR) assay and microscale thermophoresis (MST) assay, respectively. LAGi-DEL blocks the LAG-3/MHC-II interaction, with an EC50 of 138 nM. LAGi-DEL restores T cell activation, enhances IFN-γ secretion and promotes immune-mediated cytotoxicity. LAGi-DEL can be used in the research of acute myeloid leukemia, lung cancer and melanoma.
    LAGi-DEL
  • HY-N17239
    Oleracone
    		Inhibitor
    Oleracone is a type of alkaloid that can be found in Portulaca oleracea L.. Oleracone exhibits a significant anti-inflammatory effect in the RAW 264.7 macrophage model induced by LPS (HY-D1056), capable of inhibiting NO production and significantly suppressing the secretion of pro-inflammatory cytokines TNF-α, IL-6, and prostaglandin E₂ (PGE₂). Oleracone can be used for the study of inflammatory diseases.
    Oleracone
  • HY-P11161
    Fowlicidin-2
    		Inhibitor
    Fowlicidin-2 is an alpha helical antibacterial peptide. Fowlicidin-2 can significantly inhibit the production of TNF-α and NO. Fowlicidin-2 can be used in the study of infectious conditions and sepsis.
    Fowlicidin-2
  • HY-177155
    p38α-IN-10
    		Inhibitor
    P38α-IN-10 (Compound 8) is an orally active inhibitor of p38α, with an IC₅₀ of 230 nM. P38α-IN-10 has an inhibitory effect on TNF production induced by LPS (HY-D1056). P38α-IN-10 can be used for the study of diseases such as rheumatoid arthritis and septic shock.
    p38α-IN-10
  • HY-P11616
    WK2
    		Inhibitor
    WK2 is an antibacterial agent. WK2 reduces serum TNF-α production induced by Bacterial infection. WK2 reduces wound size and promotes tissue repair in a skin wound infection model. WK2 exerts anti-inflammatory effects in a pneumonia model. WK2 can be used for research on infectious diseases such as pneumonia caused by bacterial infection.
    WK2
  • HY-155820
    Anti-inflammatory agent 54
    		Inhibitor
    Anti-inflammatory agent 54 (compound 9c) is a derivative of Coixol and has anti-inflammatory activity. Anti-inflammatory agent 54 inhibits the NF-κB pathway and downregulates the expression of iNOS, TNF-α, IL-6 and IL-1β. Anti-inflammatory agent 54 inhibits LPS-induced nitric oxide (NO) production in RAW264.7 macrophages (IC50: 2.4 μM) and exerts in vivo anti-inflammatory activity in a mouse auricular edema model.
    Anti-inflammatory agent 54
  • HY-Y0148R
    10-Hydroxydecanoic acid (Standard)
    		Inhibitor
    10-Hydroxydecanoic acid (Standard) is the analytical standard of 10-Hydroxydecanoic acid. This product is intended for research and analytical applications. 10-Hydroxydecanoic acid (10-HDAA) is a saturated fatty acid derived from 10-hydroxy-trans-2-decenoic acid, which can be isolated from royal jelly. 10-Hydroxydecanoic acid exhibits various biological activities, including anti-inflammatory, insecticidal, anti-malarial, and anti-Leishmania properties, as well as enhancing antigen-specific immune responses. The anti-inflammatory effects of 10-Hydroxydecanoic acid are primarily mediated by inhibiting the activation of NF-κB and the translation of interferon regulatory factor 1 (IRF-1), which reduces the production of interleukin 6 (IL-6) and nitric oxide (NO) in inflammatory cells. Additionally, 10-Hydroxydecanoic acid alleviates neuroinflammatory responses through the p53-autophagy pathway and the p53-NLRP3 pathway. Finally, 10-Hydroxydecanoic acid enhances antigen-specific immune responses by promoting the effective uptake of antigens by microfold cells[1][2][3][4][5].
    10-Hydroxydecanoic acid (Standard)
  • HY-P99133
    Anti-Mouse Fas Ligand Antibody (MFL3)
    		Inhibitor
    Anti-Mouse Fas Ligand Antibody (MFL3) is an anti-mouse Fas Ligand IgG antibody inhibitor derived from host Armenian Hamster. Anti-Mouse Fas Ligand Antibody (MFL3) can block Fas Ligand (FasL). Anti-Mouse Fas Ligand Antibody (MFL3) can be used for the researches of cancer and immunology.
    Anti-Mouse Fas Ligand Antibody (MFL3)
  • HY-N0512R
    Loganin (Standard)
    		Inhibitor
    Loganin (Standard) is the analytical standard of Loganin. This product is intended for research and analytical applications. Loganin is a type of iridoid glycoside compound that possesses anti-inflammatory, antioxidant, and antitumor properties, and offers protective effects against acute lung injury and pulmonary fibrosis. Loganin exerts its protective effects against LPS (HY-D1056)-mediated inflammation and oxidative stress by upregulating the Nrf2/HO-1 signaling pathway, and it reduces neuroinflammation caused by spinal cord injury (SCI).
    Loganin (Standard)
  • HY-W008829
    N,N-Diethylacetamide
    		Inhibitor 99.68%
    N,N-Diethylacetamide is a polar solvent widely used in film and fiber manufacturing, as well as in laboratories as a carrier for water-insoluble chemicals. N,N-Diethylacetamide exerts potent anti-inflammatory effects by inhibiting the NF-κB pathway, suppressing the expression of NO and iNOS, and downregulating key inflammatory cytokines such as TNF-α and IL-6, without affecting the MAPK pathway. N,N-Diethylacetamide can be used to study inflammatory preterm birth.
    N,N-Diethylacetamide
  • HY-N8712
    Umckalin
    		Inhibitor
    Umckalin is Coumarin (HY-N0709) derivative that exhibits anti-inflammatory properties. Umckalin reduces phosphorylation of p38 MAPK, JNK, and ERK, lowers TNF-α, IL-6, IL-1β, NO, and PGE2 production. Umckalin can be used for the research of chronic inflammatory diseases.
    Umckalin
  • HY-15509
    Semapimod
    		Inhibitor
    Semapimod, an inhibitor of proinflammatory cytokine production, can inhibit TNF-α, IL-1β, and IL-6. Semapimod inhibits TLR4 signaling (IC50≈0.3 μM). Semapimod inhibits p38 MAPK and nitric oxide production in macrophages. Semapimod has potential in a variety of inflammatory and autoimmune disorders.
    Semapimod
  • HY-P991666
    BMS-986090
    		Inhibitor
    BMS-986090 is a humanized monoclonal antibody antagonist targeting CD40. BMS-986090 is promising for research of autoimmune diseases such as systemic lupus erythematosus (SLE) and focal segmental glomerulosclerosis (FSGS).
    BMS-986090
  • HY-171780
    ASP9831
    		Inhibitor
    ASP9831 is an orally active PDE4 inhibitor. ASP9831 inhibits LSP-induced TNF-α production and has anti-inflammatory activity. ASP9831 can be used in fatty liver disease research.
    ASP9831
  • HY-P99692
    Lenercept
    		Inhibitor
    Lenercept (Ro 45-2081) is a recombinant fusion protein that consists of the soluble TNF-receptor (p55) linked to the Fc portion of human IgG1.
    Lenercept
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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