1. Signaling Pathways
  2. Apoptosis
  3. 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 (47):

Cat. No. Product Name Effect Purity
  • HY-A0003
    Lenalidomide Inhibitor 99.98%
    Lenalidomide是用作免疫调节药物的 TNF-α 抑制剂。它还具有抗血管生成活性。
  • HY-16046
    Rimiducid Activator 99.39%
    Rimiducid (AP1903) 是二聚化剂,其通过交联 FKBP 结构域起作用,启动 Fas 信号传导,引起凋亡
  • HY-10984
    Pomalidomide Inhibitor 99.86%
    Pomalidomide是一种抗血管生成剂和免疫调节剂。 Pomalidomide在LPS刺激的人PBMC中抑制 TNF-α 释放,IC50 为13 nM。
  • HY-N0822
    Shikonin Inhibitor 99.80%
    Shikonin是中草药紫草的主要成分。 Shikonin显示出各种生物活性,包括抑制TNF-αNF-κBHIV-1
  • HY-15615A
    TIC10 Agonist 99.68%
    TIC10是一种有效,有口服活性,稳定的 TRAIL 诱导剂,其通过抑制 AktERK 起作用,从而激活Foxo3a并显着诱导细胞表面TRAIL。
  • HY-111255
    SPD304 Inhibitor >99.0%
    SPD304是肿瘤坏死因子α (TNFα) 的选择性抑制剂,能够促进肿瘤坏死因子三聚体的分离,从而阻断其与受体间的相互作用,其体外抑制肿瘤坏死因子α和受体1间结合的IC50 值为22 µM。SPD304毒性高,不能用于体内。
  • HY-108847
    Etanercept Inhibitor
    Etanercept (Enbrel) 是一种肿瘤坏死因子(TNF)抑制剂,用于治疗类风湿性关节炎,强直性脊柱炎,银屑病关节炎和斑块状银屑病。
  • HY-120934
    C25-140 Inhibitor
    C25-140 是一种一流的 TRAF6–Ubc13 相互作用的抑制剂,直接与 TRAF6 结合,阻断 TRAF6 和 Ubc13 的相互作用,从而降低 TRAF6 活性。C25-140 扩展了研究泛素系统对免疫信号的影响,并强调了 TRAF6 E3 连接酶活性在银屑病和类风湿性关节炎中的重要性。
  • HY-13812
    QNZ Inhibitor 98.46%
    QNZ (EVP4593) 强抑制 NF-κB 转录激活和 TNF-α 产生,IC50 分别为 11 和 7 nM。QNZ (EVP4593) 是一种保护神经的钙池操纵的钙通道 (SOC) 抑制剂。
  • HY-N0182
    Fisetin Inhibitor 98.02%
    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-32018
    Cot inhibitor-2 Inhibitor 99.20%
    Cot 抑制剂-2是COT/Tpl2抑制剂。
  • HY-A0003B
    Lenalidomide hemihydrate Inhibitor 99.82%
    Lenalidomide是沙利度胺类似物,其抑制肿瘤血管生成,肿瘤增殖和肿瘤分泌细胞因子,包括TNF-αIL 6
  • 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-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-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-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-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-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-N0604
    Ginsenoside Rh1 Inhibitor 98.17%
    Ginsenoside Rh1 (Prosapogenin A2; Sanchinoside B2; Sanchinoside Rh1) 是从 Panax Ginseng 根部分离的。 Ginsenoside Rh1 抑制 PPAR-γTNF-αIL-6IL-1β 的表达。
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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