Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of IκBα in anti-inflammatory effect of gemfibrozil in microglia
Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of IκBα in anti-inflammatory effect of gemfibrozil in microglia
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DOI：
10.4049/jimmunol.179.6.4142
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发表时间：
2007-09-15
影响因子：
4.4
通讯作者：
Pahan, Kalipada
中科院分区：
文献类型：
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作者：
Jana, Malabendu;Jana, Arundhati;Pahan, Kalipada
目前的研究强调了PI3K在小鼠小胶质细胞中介导吉非罗齐（一种处方降脂药）抗炎作用中的重要性。吉非非齐抑制lps诱导的小鼠BV-2小胶质细胞和原代小胶质细胞诱导NO合成酶（iNOS）和促炎细胞因子的表达。通过在小胶质细胞中过表达野生型和显性阴性结构的过氧化物酶体增殖物激活受体-a (PPAR-a)，并从ppar - α(-/-)小鼠中分离原代小胶质细胞，我们已经证明了gemfibrozil抑制了独立于PPAR-a的小胶质细胞的激活。有趣的是，吉非齐尔诱导了p85 α相关PI3K的激活（p110 β，而不是p110 α），化学抑制剂或显性阴性突变体对PI3K的抑制作用取消了吉非齐尔的抑制作用。相反，p110组成型活性突变体的过表达增强了吉非罗齐对lps诱导的促炎分子表达的抑制作用。同样，gemfibrozil也抑制纤维淀粉样蛋白β (A β)-、朊蛋白肽(PrP)-、dsRNA (poly IC)-、HIV-1 Tat-和1-甲基-4-苯基吡啶(MPP+)-诱导的iNOS的小胶质表达，但不抑制ifn - γ -。对PI3K的抑制也消除了吉非罗齐对A β -、PrP-、poly -、Tat-和MPP+ -诱导的小胶质细胞iNOS表达的抑制作用。NF-kappa B激活参与LPS-、A β -、PrP-、poly -、Tat-和MPP+-，但不参与ifn - γ -，诱导小胶质细胞iNOS表达，刺激I κ B α表达，并通过PI3K途径抑制NF-kappa B α激活，表明吉非齐尔通过PI3K介导的I κ B α上调抑制NF-kappa B的激活和小胶质细胞中促炎分子的表达。
The present study underlines the importance of PI3K in mediating the anti-inflammatory effect of gemfibrozil, a prescribed lipid-lowering drug for humans, in mouse microglia. Gemfibrozil inhibited LPS-induced expression of inducible NO synthase (iNOS) and proinflammatory cytokines in mouse BV-2 microglial cells and primary microglia. By overexpressing wild-type and dominant-negative constructs of peroxisome proliferator-activated receptor-a (PPAR-a) in microglial cells and isolating primary microglia from PPAR-alpha(-/-) mice, we have demonstrated that gemfibrozil inhibits the activation of microglia independent of PPAR-a. Interestingly, gemfibrozil induced the activation of p85 alpha-associated PI3K (p110 beta but not p110 alpha) and inhibition of that PI3K by either chemical inhibitors or dominant-negative mutants abrogated the inhibitory effect of gemfibrozil. Conversely, overexpression of the constitutively active mutant of p110 enhanced the inhibitory effect of gemfibrozil on LPS-induced expression of proinflammatory molecules. Similarly, gemfibrozil also inhibited fibrillar amyloid beta (A beta)-, prion peptide (PrP)-, dsRNA (poly IC)-, HIV-1 Tat-, and 1-methyl-4-phenylpyridinium (MPP+)-, but not IFN-gamma-, induced microglial expression of iNOS. Inhibition of PI3K also abolished the inhibitory effect of gemfibrozil on A beta-, PrP-, poly IC-, Tat-, and MPP+ -induced microglial expression of iNOS. Involvement of NF-kappa B activation in LPS-, A beta-, PrP-, poly IC-, Tat-, and MPP+-, but not IFN-gamma-, induced microglial expression of iNOS and stimulation of I kappa B alpha expression and inhibition of NF-kappa B activation by gemfibrozil via the PI3K pathway suggests that gemfibrozil inhibits the activation of NF-kappa B and the expression of proinflammatory molecules in microglia via PI3K-mediated up-regulation of I kappa B alpha.