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-N0405R
    Orientin (Standard)
    		Inhibitor
    Orientin (Standard) is the analytical standard of Orientin. This product is intended for research and analytical applications. Orientin is a neuroprotective agentinhibits which has anti-inflammation, anti-oxidative, anti-tumor, and cardio protection properties. Orientin inhibits the levels of IL-6, IL-1β and TNF-α. Orientin increases IL-10 level. Orientin exhibits neuroprotective effect by inhibits TLR4 and NF-kappa B signaling pathway. Orientin can used in study neuropathic pain.
    Orientin (Standard)
  • HY-146419
    Anti-inflammatory agent 20
    		Inhibitor
    Anti-inflammatory agent 20 (compound 5a) is a potent inhibitor of NO activity. Anti-inflammatory agent 20 shows anti-inflammatory activity. Anti-inflammatory agent 20 suppresses LPS-induced inflammation via inhibiting the activation of NF-κB and MAPK signaling and thereby reducing IL-6, TNF-α, iNOS, and COX-2 upregulation.
    Anti-inflammatory agent 20
  • HY-168130
    TNF-α/IL-1β-IN-1
    		Inhibitor
    TNF-α/IL-1β-IN-1 (compund 11a) is an anti-inflammatory agent that reduces the expression of TNF-α and IL-1β, inhibits oxidative stress and cardiomyocyte apoptosis, has good activity against septic myocardial injury, and improves myocardial blood supply in vivo.
    TNF-α/IL-1β-IN-1
  • HY-173290
    PDE4D inhibitor 1
    		Inhibitor
    PDE4-IN-1 is a PDE4 inhibitor with high potency (IC50 : 8.6 nM) and selectivity over other PDE subtypes. PDE4-IN-1 inhibits the release of inflammatory cytokines and chemokines. PDE4-IN-1 greatly restores impaired cAMP-CREB signaling pathway. PDE4-IN-1 inhibits proliferation and promotes differentiation to reverse the formation of psoriasis.
    PDE4D inhibitor 1
  • HY-175182
    IDO1-IN-27
    		Inhibitor
    IDO1-IN-27 (Compound I-1) is a Indoleamine 2,3-Dioxygenase 1 (IDO1) inhibitor with an IC50 of 0.3951  μM for recombinant hIDO1. IDO1-IN-27 also inhibits hIDO1 expression in HeLa cells (EC50: 62 nM). IDO1-IN-27 effectively stimulates T cell proliferation by reducing the mRNA expression of pro-inflammatory factors (TNF-α, IL-6, and IL-1β) while concurrently inhibiting LLC cells growth.
    IDO1-IN-27
  • HY-N16620
    Gnetucleistol F
    		Inhibitor
    Gnetucleistol F is a stilbenolignan isolated from Gnetum cleistostachyum with anti-inflammatory activity. Gnetucleistol F exhibits potent inhibitory activities on TNF-α and malondialdehyde (MDA) with IC50 values of 10.3 and 6.36 μM, respectively. Gnetucleistol F can be used for anti-inflammatory research.
    Gnetucleistol F
  • HY-170686
    BRD4 Inhibitor-38
    		Inhibitor
    BRD4 Inhibitor-38 (Compound 25) is an orally active inhibitor of BRD4 with IC50 values of 3.64 μM and 0.12 μM against BRD4 BD1 and BRD4 BD2, respectively. BRD4 Inhibitor-38 also exhibits anti-inflammatory activity, with an IC50 value of 1.98 μM for inhibiting nitric oxide (NO) production.
    BRD4 Inhibitor-38
  • HY-P0071
    F 991
    		Inhibitor
    F 991 is an immunoglobulin free light chain antagonist. F 991 can significantly reduce the levels of pro-inflammatory cytokines (TNF-α and IL-6). F 991 can be used for research on allergic conditions.
    F 991
  • HY-N15708
    Dichotomine C
    		Inhibitor
    Dichotomine C ((R)-(-)-Dichotomine C) is a β-carboline-type alkaloid with antiallergic effects. Dichotomine C inhibits the release of β-hexosaminidase in RBL-2H3 cells with an IC50 of 62 μM. Dichotomine C inhibits the releases of antigen-IgE-mediated TNF-α and IL-4 in RBL-2H3 cells with IC50s of 19 μM and 15 μM, respectively. Dichotomine C can be used for the study of type I allergic reactions.
    Dichotomine C
  • HY-N15570
    2-O-Methylatromentin
    		Inhibitor
    2-O-Methylatromentin is an anti-neuroinflammatory agent. 2-O-Methylatromentin shows inhibitory activity on the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in Lipopolysaccharides (HY-D1056) (LPS) -induced BV-2 microglial cells. 2-O-Methylatromentin can be used for the study of neuroinflammatory related diseases.
    2-O-Methylatromentin
  • HY-147247
    Fosimdesonide
    		Inhibitor
    Fosimdesonide, a small molecule of adalimumab fosimdesonide, is a potent immunomodulator. Fosimdesonide shows anti-inflammatory activity.
    Fosimdesonide
  • HY-183569
    CSF1R-IN-27
    		Inhibitor
    CSF1R-IN-27 is a CSF1R inhibitor with oral effectiveness, kinome-wide selective profile, low cellular cytotoxicity, and CSF1R IC50 values of 19 nM, 88 nM, 173 nM, 797 nM, 1448 nM, and >3000 nM. CSF1R-IN-27 suppresses M-CSF-induced phosphorylation of CSF1R, AKT, and ERK in macrophages, and inhibits hepatic p-CSF1R/p-AKT/p-ERK signaling. CSF1R-IN-27 reduces serum transaminase levels, improves hepatic histopathology, alleviates inflammatory cell infiltration, and decreases circulating TNF-α and IL-6 levels. CSF1R-IN-27 can be used for the research of acute liver injury.
    CSF1R-IN-27
  • HY-162599
    Spirohypertone B
    		Inhibitor
    Spirohypertone B is a potent Tumor necrosis factor-α (TNF-α) inhibitor. Spirohypertone B protects L929 cells from death induced by co-incubation with TNF-α and Actinomycin D (HY-17559).
    Spirohypertone B
  • HY-149087
    MR2938
    		Inhibitor
    MR2938 is a potent AChE inhibitor, with an IC50 of 5.04 μM. MR2938 also suppresses NO production obviously (IC50 = 3.29 μM). MR2938 suppresses the neuroinflammation through blocking MAPK/JNK and NF-κB signaling pathways. MR2938 can be used for Alzheimer’s disease (AD) research.
    MR2938
  • HY-146560
    Xanthine oxidase-IN-6
    		Inhibitor
    Xanthine oxidase-IN-6 (Compound 6c) is a potent, orally active, mixed-type xanthine oxidase (XOD) inhibitor with an IC50 value of 1.37 µM. Xanthine oxidase-IN-6 shows strong anti-hyperuricemia and renal protective activity.
    Xanthine oxidase-IN-6
  • HY-183537
    KSI-028
    		Inhibitor
    KSI-028 is a STING inhibitor. KSI-028 disrupts STING-mediated signal transduction, reduces IFN-β and pro-inflammatory cytokine (IL-6, IL-1β and TNF-α) production. KSI-028 inhibits the phosphorylation of STING, TBK1, IRF3, and STAT1. KSI-028 attenuates renal and hepatic injury in a Cisplatin (HY-17394)-induced acute kidney injury mouse model.
    KSI-028
  • HY-170723
    JAK-IN-39
    		Inhibitor
    JAK-IN-39 (compound 11) is a JAK inhibitor that suppresses JAK1, JAK2, JAK3 with IC50 values of 0.05, 1.18, and 0.03 nM, respectively. JAK-IN-39 can inhibit the viability of TF-1 cells and also suppress the production of lymphocyte TNFα and INFγ in vitro.
    JAK-IN-39
  • HY-117710B
    AD-35
    		Inhibitor
    AD-35 is an orally active anti-Alzheimer's disease (AD) agent with moderate AChE inhibitory activity and metal ion chelating ability. AD-35 exhibits IC50 values for AChE and BuChE of 793 nM and 31428 nM, respectively. AD-35 can form chelates with Cu²⁺ and Fe³⁺, but its chelating ability for Zn²⁺ is relatively weak. AD-35 can inhibit Aβ aggregation and disassemble the formed Aβ aggregates, and inhibit Aβ-induced ERK phosphorylation. AD-35 inhibits neuroinflammation in AD rat models and demonstrates a strong effect in improving cognitive function.
    AD-35
  • HY-W750980
    β-Bisabolol
    		Inhibitor
    β-Bisabolol is a potent anti-inflammatory agent that can be found in cotton gin trash. β-Bisabolol inhibits the production of nitric oxide (NO), pGE2, TNF-α, IL-6, and IL-8 in LPS (HY-D1056)-stimulated macrophages and fibroblast cells. β-Bisabolol can be used for the research on inflammatory conditions.
    β-Bisabolol
  • HY-107272
    Chuanbeinone
    		Inhibitor
    Chuanbeinone (22-Epidelavinone) is an orally active alkaloid found in Fritillaria pallidiflora. Chuanbeinone shows cytotoxicity against mutiple cancer cells and can induces apoptosis and S phase arrest. Chuanbeinone downregulates Bcl-2, upregulates Bax, and activates caspase-3. Chuanbeinone exerts anti-inflammatory and antitussive effects by reducing pro-inflammatory cytokine (IL-1β, IL-6 and TNF-α) production and mRNA expression, and inhibiting TRIF-, MyD88-, NF-κB-, and MAPK-dependent signaling pathways. Chuanbeinone inhibits AChE and BChE with IC50 values of 7.7 and 0.7 μM. Chuanbeinone can be used for the researches of lung carcinoma, cough, inflammatory diseases.
    Chuanbeinone
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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