1. Apoptosis
  2. TNF Receptor

TNF Receptor

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.

View TNF Receptor Pathway Map

TNF Receptor 相关产品 (42):

Cat. No. Product Name Effect Purity
  • HY-A0003
    Lenalidomide Inhibitor 99.98%
    Lenalidomide 是一种有效的 TNF-α 抑制剂,具有抗血管增生作用。Lenalidomide 作为连接酪蛋白激酶 1A1 (CKIα) 与人 E3 连接酶 cereblon 的蛋白质稳态调节剂 (PHM) 起作用。
  • HY-16046
    AP1903 Activator 99.05%
    AP1903 是一种同源二聚体,结合到 FKBP,诱导培养中的工程细胞系HT1080发凋亡和死亡,EC50 为 0.1 nM,这种作用具有剂量依赖性。AP1903 诱导 Fas 激活。Fas 受体也称为肿瘤坏死因子受体超家族成员 6 (TNFRSF6)。
  • HY-10984
    Pomalidomide Inhibitor 99.86%
    Pomalidomide 作用于 LPS 刺激的人 PBMC 细胞,抑制 TNF-α 释放,IC50 为 13 nM。
  • HY-N0822
    Shikonin Inhibitor 99.64%
    Shikonin 是 TMEM16A 氯化物通道的抑制剂,其 IC50 值为 6.5 μM。Shikonin 也是一种特异性的 PKM2 抑制剂,而且可以抑制肿瘤坏死因子-α (TNF-α),阻止核因子-κB (NF-κB) 通路的激活。
  • HY-15615A
    TIC10 Agonist 99.68%
    TIC10 是一种有效的 TRAIL 诱导剂,也抑制 AktERK 活性。
  • HY-110203
    R-7050 Antagonist 98.83%
    R-7050 是一种肿瘤坏死因子受体 (TNFR) 拮抗剂,对 TNFα 具有更高选择性。
  • HY-N0066
    Eucalyptol Inhibitor >98.0%
    Eucalyptol 是 5-HT3 受体, 钾通道, TNF-αIL-1β 的抑制剂。
  • HY-N0509
    Astilbin Inhibitor 99.43%
    Astilbin 是一种黄酮类化合物,可从 Smilax glabra 根茎中分离。Astilbin 增强 NRF2 活化。Astilbin 还抑制 TNF-α 表达和 NF-κB 活化。
  • HY-13812
    QNZ Inhibitor 98.46%
    QNZ 强抑制 NF-κB 转录激活和 TNF-α 产生,IC50 分别为 11 和 7 nM。QNZ 是一种保护神经的钙池操纵的钙通道 (SOC) 抑制剂。
  • HY-A0003B
    Lenalidomide hemihydrate Inhibitor 99.82%
    Lenalidomide hemihydrate 是一种有效的 TNF-α 抑制剂,具有抗血管增生作用。Lenalidomide 作为连接酪蛋白激酶 1A1 (CKIα) 与人 E3 连接酶 cereblon 的蛋白质稳态调节剂 (PHM) 起作用。
  • HY-N0182
    Fisetin Inhibitor >98.0%
    Fisetin是一种在许多水果和蔬菜中发现的天然黄酮醇,具有多种益处,如抗氧化,抗癌,神经保护作用。
  • HY-P0224
    N-Formyl-Met-Leu-Phe Inhibitor 99.46%
    N-Formyl-Met-Leu-Phe (fMLP; N-Formyl-MLF) 是一种趋化肽和N-甲酰基肽受体 (FPR) 的特异性配体。报道显示N-Formyl-Met-Leu-Ph 可抑制 TNF-alpha 的分泌。
  • HY-14622
    Necrostatin 2 Inhibitor 99.97%
    Necrostatin 2 是一种有效的程序性坏死 (necroptosis) 抑制剂。作用于TNF-α处理的FADD缺陷型Jurkat T细胞,抑制程序性坏死,EC50 为 0.05 μM。
  • HY-N2027
    Taurochenodeoxycholic acid Inhibitor 99.80%
    Taurochenodeoxycholic acid是动物胆汁酸的主要生物活性物质之一。
  • HY-14622A
    Necrostatin 2 racemate Inhibitor 99.10%
    Necrostatin 2是高活性的坏死性凋亡抑制剂,EC50为50nM。
  • HY-P9908
    Adalimumab Inhibitor 98.12%
    Adalimumab 是一种人源的单克隆 IgG1 抗体,靶向肿瘤坏死因子α (TNF-α)。
  • HY-32018
    Cot inhibitor-2 Inhibitor 99.20%
    Cot 抑制剂-2是COT/Tpl2抑制剂。
  • HY-100735
    C 87 Inhibitor >98.0%
    C87是一种新型小分子TNFα抑制剂; 高效抑制TNFα诱导的细胞毒性,IC50值为8.73 μM。
  • HY-A0203
    Pentosan Polysulfate >98.0%
    Pentosan Polysulfate是一种半合成药物,用于治疗包括血栓和间质性膀胱炎在内的多种症状。
  • HY-15643A
    LY 303511 hydrochloride Activator 98.41%
    LY 303511 hydrochloride 是 是 LY294002 的一种结构类似物,但 LY303511 不抑制 PI3K。LY303511 可增强 SHEP-1 神经母细胞瘤细胞的TRAIL 敏感性。LY303511 可逆地阻断 MIN6 胰岛瘤细胞中的 K+ 电流 (IC50=64.6±9.1 μM)。
tnf-receptor-map.png

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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