Noman Abu Shadat M, Koide Naoki, Hassan Ferdaus, I-E-Khuda Imtiaz, Dagvadorj Jargalsaikhan, Tumurkhuu Gantsetseg, Islam Shamima, Naiki Yoshikazu, Yoshida Tomoaki, Yokochi Takashi
Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
Innate Immun. 2009 Feb;15(1):33-41. doi: 10.1177/1753425908099317.
The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF-alpha production. Thalidomide prevented the activation of nuclear factor (NF)-KB by down-regulating phosphorylation of inhibitory KB factor (IKB), and IKB kinase (IKK)-alpha and IKK-beta Moreover, thalidomide inhibited LPS-induced phosphorylation of AKT, p38 and stress-activated protein kinase (SAPK)/JNK. The expression of myeloid differentiation factor 88 (MyD88) protein and mRNA was markedly reduced in thalidomide-treated RAW 264.7 cells but there was no significant alteration in the expression of interleukin-1 receptor-associated kinase (IRAK) 1 and TNF receptor-associated factor (TRAF) 6 in the cells. Thalidomide did not affect the cell surface expression of Toll-like receptor (TLR) 4 and CD14, suggesting the impairment of intracellular LPS signalling in thalidomide-treated RAW 264.7 cells. Thalidomide significantly inhibited the TNF-alpha production in response to palmitoyl-Cys(RS)-2,3-di(palmitoyloxy) propyl)-Ala-Gly-OH (Pam(3)Cys) as a MyD88-dependent TLR2 ligand. Therefore, it is suggested that thalidomide might impair LPS signalling via down-regulation of MyD88 protein and mRNA and inhibit LPS-induced TNF-alpha production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.
利用RAW 264.7小鼠巨噬细胞样细胞研究了沙利度胺对脂多糖（LPS）诱导的肿瘤坏死因子（TNF）-α产生的影响。沙利度胺显著抑制LPS诱导的TNF-α产生。沙利度胺通过下调抑制性κB因子（IκB）、IκB激酶（IKK）-α和IKK-β的磷酸化来阻止核因子（NF）-κB的激活。此外，沙利度胺抑制LPS诱导的AKT、p38和应激激活蛋白激酶（SAPK）/JNK的磷酸化。在经沙利度胺处理的RAW 264.7细胞中，髓样分化因子88（MyD88）蛋白和mRNA的表达明显降低，但细胞中白细胞介素-1受体相关激酶（IRAK）1和TNF受体相关因子（TRAF）6的表达没有显著改变。沙利度胺不影响Toll样受体（TLR）4和CD14的细胞表面表达，提示经沙利度胺处理的RAW 264.7细胞中细胞内LPS信号传导受损。沙利度胺显著抑制对棕榈酰-Cys（RS）-2,3-二（棕榈酰氧基）丙基）-丙氨酸-甘氨酸-OH（Pam（3）Cys）作为MyD88依赖性TLR2配体的反应中TNF-α的产生。因此，提示沙利度胺可能通过下调MyD88蛋白和mRNA损害LPS信号传导并抑制LPS诱导的TNF-α产生。讨论了沙利度胺诱导MyD88下调的推测机制。
