A novel mechanism for inhibition of lipopolysaccharide-induced proinflammatory cytokine production by valproic acid
A novel mechanism for inhibition of lipopolysaccharide-induced proinflammatory cytokine production by valproic acid
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DOI：
10.1016/j.intimp.2014.02.032
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发表时间：
2014-05-01
影响因子：
5.6
通讯作者：
Yokochi, Takashi
中科院分区：
文献类型：
--
作者：
Jambalganiin, Ulziisaikhan;Tsolmongyn, Bilegtsaikhan;Yokochi, Takashi
采用小鼠RAW 264.7巨噬细胞样细胞研究丙戊酸（VPA）对脂多糖（LPS）诱导的炎症反应的抑制作用。WA预处理减弱LPS诱导的磷脂酰肌醇3-激酶（PI 3 K）和Akt的磷酸化，但不包括核因子（NF）-κ B和丝裂原活化蛋白激酶。VPA降低了MDM 2（一种泛素连接酶）的磷酸化，然后阻止了LPS诱导的p53降解，随后增强了p53表达。此外，p53小干扰RNA（siRNA）消除了VPA对LPS诱导的NF-κ B p65转录激活和进一步LPS诱导的肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6产生的抑制作用。WA可抑制LPS诱导的第10号染色体缺失的磷酸酶和张力蛋白同源物（PIEN）的降解，并上调PTEN的表达。综上所述，VPA通过受损的PI 3 K/Akt/MDM 2激活和增强的p53表达下调LPS诱导的NF-κ B依赖性转录活性。WA抑制LPS诱导的炎症反应的详细机制进行了讨论。(C)© 2014 Elsevier B. V.保留所有权利。
The inhibitory effect of valproic acid (VPA) on lipopolysaccharide (LPS)-induced inflammatory response was studied by using mouse RAW 264.7 macrophage-like cells. WA pretreatment attenuated LPS-induced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt, but not nuclear factor (NF)-kappa B and mitogen-activated protein kinases. VPA reduced phosphorylation of MDM2, an ubiquitin ligase and then prevented LPS-induced p53 degradation, followed by enhanced p53 expression. Moreover, p53 small interfering RNA (siRNA) abolished the inhibitory action of VPA on LPS-induced NF-kappa B p65 transcriptional activation and further LPS-induced tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production. WA prevented LPS-induced degradation of phosphatase and tensin homologue deleted on chromosome ten (PIEN) and up-regulated the PTEN expression. Taken together, VPA was suggested to down-regulate LPS-induced NF-kappa B-dependent transcriptional activity via impaired PI3K/Akt/MDM2 activation and enhanced p53 expression. A detailed mechanism for inhibition of LPS-induced inflammatory response by WA is discussed. (C) 2014 Elsevier B.V. All rights reserved.