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-P99663
    Inezetamab
    		Inhibitor 99.77%
    Inezetamab is a bispecific anti-CD40 and anti-MSLN IgG1 monoclonal antibody.
    Inezetamab
  • HY-176192
    SMU-14a
    		Inhibitor
    SMU-14a is a selective Toll-like receptor 3 (TLR3) inhibitor wirh an IC50 of 0.18 μM. SMU-14a reduces phosphorylation of p65, ERK, and TBK1 via NF-κB, MAPK, and IRF3 signaling pathways. SMU-14a inhibits IL-6 secretion in mouse peritoneal macrophages, downregulates TNF-α in human peripheral blood monocytes and decreases serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. SMU-14a can be used for the research of acute hepatitis.
    SMU-14a
  • HY-178041
    BRD4-BD1/2-IN-3
    		Inhibitor 99.52%
    BRD4-BD1/2-IN-3 (Compound B6) is a selective BRD4 BD2 inhibitor with an IC50 of 0.41  nM for BRD4 BD2 over BRD4 BD1. BRD4-BD1/2-IN-3 significantly inhibits the LPS (HY-D1056)-induced expression of IL-6. BRD4-BD1/2-IN-3 shows anti-inflammatory activities by modulating the TNF and NF-κB signaling pathway. BRD4-BD1/2-IN-3 can be used for inflammatory diseases research.
    BRD4-BD1/2-IN-3
  • HY-N1965
    Gaultherin
    		Inhibitor 99.44%
    Gaultherin is an orally active non-steroidal anti-inflammatory agent. Gaultherin selectively inhibits NF-κB, MAPK, COX-2 (IC50 = 0.35 mg/mL), LOX (IC50 = 0.56 mg/mL) and HYAL (IC50 = 28.58 μg/mL) to exert anti-inflammatory, antipyretic and analgesic effects. Gaultherin exhibits modest direct antioxidant capacity, greater in cell-based models. Gaultherin does not affect COX-1 so that avoids the common gastrointestinal side effects of Aspirin (HY-14654).
    Gaultherin
  • HY-163035
    EM-163
    		Inhibitor
    EM-163 is a summative BB-Loop analog. EM-163 can alleviate inflammation and prevent death from toxic shock by targeting the TIR domain of MyD88. EM-163 can be used in the study of SEB poisoning (SEB: Staphylococcal enterotoxin B).
    EM-163
  • HY-P991120
    Balertatug
    		Inhibitor 98.84%
    Balertatug is a human IgG1K antibody targeting CD70. The corresponding isotype control is: Human lgG1 kappa, lsotype Control (HY-P99001).
    Balertatug
  • HY-P992132
    Solaprubart
    		Inhibitor
    Solaprubart is a humanized IgG1-κ monoclonal antibody targeting TNFSF4/OX40L. Solaprubart regulates immune homeostasis by blocking the OX40L-OX40 signaling pathway and can be used for the research of autoimmune diseases such as atopic dermatitis.
    Solaprubart
  • HY-P10399
    KGYY15
    		Inhibitor 99.19%
    KGYY15 (Mouse KGYY15) is a CD40 targeting peptide, which weakly inhibits the CD40-CD40L interaction with IC50 of more than 1mM. KGYY15 activates 33% NF-κB pathway at 100 μM.
    KGYY15
  • HY-U00179
    CDC801
    		Inhibitor 98.94%
    CDC801 is a potent and orally active phosphodiesterase 4 (PDE4) and tumor necrosis factor-α (TNF-α) inhibitor with IC50 of 1.1 μM and 2.5 μM, respectively.
    CDC801
  • HY-N11011
    Withaphysalin A
    		Inhibitor 98%
    Withaphysalin A is a withanolide compound with anti-inflammatory and antioxidant activities. Withaphysalin A inhibits LPS (HY-D1056)-induced nuclear translocation of NF-κB p65, as well as phosphorylation of STAT3, ERK, JNK and p38 MAPK. Withaphysalin A upregulates the expression of HO-1. Withaphysalin A inhibits LPS-induced production of NO, PGE2, IL-1β, IL-6 and TNF-α. Withaphysalin A downregulates LPS-induced expression of iNOS and COX-2. Withaphysalin A interacts with B-cell activating factor protein (BAFF) to exert inhibitory effects. Withaphysalin A exhibits ELOVL6 inhibitory activity. Withaphysalin A can be used in the research of inflammatory diseases, nephrotic syndrome and chronic myeloid leukemia.
    Withaphysalin A
  • HY-P990269
    Anti-Mouse CD40L/CD154 (LALA-PG) Antibody (MR-1)
    		Inhibitor
    Anti-Mouse CD40L/CD154 (LALA-PG) Antibody (MR-1) is a mouse-derived IgG2a κ type antibody inhibitor, targeting to mouse CD40L/CD154. Anti-Mouse CD40L/CD154 (LALA-PG) Antibody (MR-1) is a chimeric version of the original MR-1 antibody (HY-P990134). The variable domain sequences are identical to the original MR-1 but the constant region sequences have been switched from Armenian hamster IgG to mouse IgG2a. Anti-Mouse CD40L/CD154 (LALA-PG) Antibody (MR-1) contains a LALA-PG mutation in the Fc fragment rendering it unable to bind to endogenous Fcγ receptors. Anti-Mouse CD40L/CD154 (LALA-PG) Antibody (MR-1) blocks CD40/CD40L signaling. Anti-Mouse CD40L/CD154 (LALA-PG) Antibody (MR-1) can be used for researches of cancer, inflammation and immunology.
    Anti-Mouse CD40L/CD154 (LALA-PG) Antibody (MR-1)
  • HY-P99119A
    Anti-Mouse 4-1BB/CD137 (LALA-PG) Antibody (LOB12.3)
    		Inhibitor 98.44%
    Anti-Mouse 4-1BB/CD137 (LALA-PG) Antibody (LOB12.3) is a mouse-derived IgG2a κ type antibody agonist, targeting to mouse 4-1BB/CD137. Anti-Mouse 4-1BB/CD137 (LALA-PG) Antibody (LOB12.3) is a chimeric antibody of the original LOB12.3 antibody (HY-P990809). Anti-Mouse 4-1BB/CD137 (LALA-PG) Antibody (LOB12.3) contains the LALA-PG mutation region. Anti-Mouse 4-1BB/CD137 (LALA-PG) Antibody (LOB12.3) can be used for the researches of cancer, infection, immunology and neurological disease.
    Anti-Mouse 4-1BB/CD137 (LALA-PG) Antibody (LOB12.3)
  • HY-141582S
    Ceramide 3-d3
    		Inhibitor 98.0%
    Ceramide 3-d3 (N-Stearoyl phytosphingosine-d3) is deuterium labeled Ceramide 3. Ceramide 3 is an orally active major component of intercellular lipids in the stratum corneum of the skin, and belongs to the ceramide family. Ceramide 3 inhibits c-jun and NF-κB activation induced by Histamine (HY-B1204), and suppresses the expression of IL-4 and TNF-α. Ceramide 3 inhibits scratching behavior and vascular permeability in mice, and exhibits antihistamine effects in guinea pig ileum. Ceramide 3 improves skin barrier function, reduces transepidermal water loss, erythema and the number of circulating epidermal cells, and accelerates barrier repair of irritated or dysfunctional skin.
    Ceramide 3-d<sub>3</sub>
  • HY-N13184
    Giraldoid B
    		Inhibitor 98.49%
    Giraldoid B is an active ingredient that can be isolated from Girald Daphne Bark. Giraldoid B can inhibit LPS induced NO and b>TNF-α production in RAW264.7 and has anti-inflammatory activity.
    Giraldoid B
  • HY-158650
    10-OAHSA
    		Inhibitor 99.0%
    10-OAHSA is one of fatty acid esters of hydroxy fatty acids (FAHFAs). 10-POHSA increases glucose-stimulated insulin secretion (GSIS) at a high glucose concentration. 10-OAHSA reduces LPS (HY-D1056)-induced Tnf-α secretion in bone marrow-derived dendritic cells (BMDCs).
    10-OAHSA
  • HY-120152A
    SLP7111228 hydrochloride
    		Inhibitor 98.01%
    SLP7111228 hydrochloride is a selective sphingosine kinase 1 (SphK1) inhibitor and anti-inflammatory agent. SLP7111228 hydrochloride selectively inhibits SphK1 and reduces the production of sphingosine-1-phosphate. SLP7111228 hydrochloride decreases lipopolysaccharide-induced TNFα and IL-1β levels. SLP7111228 hydrochloride alleviates obliterative pulmonary arteriopathy, increases cardiac index and decreases total pulmonary vascular resistance index. SLP7111228 hydrochloride can be used in research related to neuroinflammatory diseases and pulmonary hypertension.
    SLP7111228 hydrochloride
  • HY-152169
    BIHC
    		Inhibitor ≥98.0%
    BIHC is a TNF blocker with anti-inflammatory activity. BIHC can significantly inhibit the proliferation of hepatocellular carcinoma (HCC) cells and exhibits potent cytotoxicity against the HepG2 cell line, capable of inducing cell apoptosis , while demonstrating relatively low toxicity towards normal hepatocytes. Additionally, BIHC can be used for research on inflammatory bowel disease (IBD).
    BIHC
  • HY-12085R
    Apremilast (Standard)
    		Inhibitor
    Apremilast (Standard) is the analytical standard of Apremilast. This product is intended for research and analytical applications. Apremilast (CC-10004) is an orally available inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4) with an IC50 of 74 nM. Apremilast inhibits TNF-α release by lipopolysaccharide (LPS) with an IC50 of 104 nM.
    Apremilast (Standard)
  • HY-W015515R
    L-Citronellol (Standard)
    		Inhibitor
    L-Citronellol ((S)-3,7-Dimethyloct-6-en-1-ol) is an analytical standard for L-Citronellol (HY-W015515). This product is intended for research and analytical applications. L-Citronellol is a natural product with anti-allergic and neuroprotective effects. L-Citronellol inhibits mast cell activation and the release of inflammatory factors by inhibiting the ERK pathway. L-Citronellol inhibits BACE1/PSEN1 and AChE, reduces TNF-α expression and lipid peroxidation, demonstrating the potential of multi-target anti-Alzheimer's disease (AD).
    L-Citronellol (Standard)
  • HY-U00142
    A-802715
    		Inhibitor 98.45%
    A802715 is a methylxanthine derivative. A802715 has a TD50 (toxic dose of 50%) of 0.9-1.1 mM.
    A-802715
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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