Vascular Biology Lab, AU-KBC Research Centre, MIT Campus, Anna University, Chennai-44, TN, India.
Curr Top Med Chem. 2012;12(13):1456-67. doi: 10.2174/156802612801784443.
Tumor necrosis factor alpha (TNF-α) is a pleiotropic inflammatory cytokine. The cytokine possesses both growth stimulating properties and growth inhibitory processes, and it appears to have self regulatory properties as well. Agents like etanercept and infliximab showed beneficial effects against rheumatoid arthritis by modulationg TNF-α proteins, however, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in different conditions. Thalidomide, an inhibitor of TNF-α protein synthesis is readily capable of crossing the blood-brain barrier and thus thalidomide and its analogs are excellent candidates for use in determining the potential value of anti-TNF-α therapies in a variety of diseases. Thalidomide blocks TNF-α expression by different possible mechanisms. Down regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), an essential transcription factor for TNF and other cytokines under thalidomide treatment leads to reduction in the TNF-α expression. Additionally, myeloid differentiation factor 88 (MyD88), an adapter protein regulates the expression of TNF under thalidomide treatment. Thalidomide treatment also leads to destruction of TNF-α mRNA thus, reducing the total expression of TNF-α protein. Thalidomide also targets reactive oxygen species (ROS) and α(1)-acid glycoprotein (AGP) to regulate TNF-α. In the present review, we discuss different possible mechanism that regulates TNF-α under thalidomide treatment. Additionally, we suggest novel strategies for the future targeting combination therapies of thalidomide and its analogs with different other anti-inflammatory drug to curb TNF-α associated diseases.
肿瘤坏死因子-α（TNF-α）是一种多效性炎症细胞因子。该细胞因子具有生长刺激和生长抑制作用，并且似乎具有自我调节特性。依那西普和英夫利昔单抗等药物通过调节 TNF-α 蛋白对类风湿关节炎显示出有益的效果，然而，这些药物在很大程度上无法穿透血脑屏障，这严重限制了它们在不同情况下的应用。沙利度胺是 TNF-α 蛋白合成的抑制剂，能够轻易穿透血脑屏障，因此沙利度胺及其类似物是用于确定抗 TNF-α 疗法在各种疾病中的潜在价值的优秀候选药物。沙利度胺通过不同的可能机制阻断 TNF-α 的表达。在沙利度胺治疗下，核因子 κB 轻链增强子的活化 B 细胞（NF-κB）的下调，是 TNF 和其他细胞因子的必需转录因子，导致 TNF-α 表达减少。此外，髓样分化因子 88（MyD88），一种调节蛋白在沙利度胺治疗下调节 TNF 的表达。沙利度胺治疗还导致 TNF-α mRNA 的破坏，从而减少 TNF-α 蛋白的总表达。沙利度胺还针对活性氧（ROS）和 α(1)-酸性糖蛋白（AGP）来调节 TNF-α。在本综述中，我们讨论了沙利度胺治疗下调节 TNF-α 的不同可能机制。此外，我们建议了未来将沙利度胺及其类似物与其他不同抗炎药物的靶向联合治疗的新策略，以抑制 TNF-α 相关疾病。
