Therapeutic targeting of Krüppel-like factor 4 abrogates microglial activation.
Therapeutic targeting of Krüppel-like factor 4 abrogates microglial activation.
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DOI：
10.1186/1742-2094-9-57
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发表时间：
2012-03-19
影响因子：
9.3
通讯作者：
Basu A
中科院分区：
文献类型：
--
作者：
Kaushik DK;Mukhopadhyay R;Kumawat KL;Gupta M;Basu A
神经炎症是由于小胶质细胞响应中枢神经系统内入侵的微生物或其他炎症刺激而激活而发生的。根据我们早期的研究结果，Krüppel 样因子 4 (Klf4) 是一种锌指转录因子，参与小胶质细胞的激活和随后促炎细胞因子、肿瘤坏死因子 α、巨噬细胞趋化蛋白 1 和白细胞介素 6 以及促炎酶、诱导型一氧化氮合酶和环氧合酶 2 的释放。 在脂多糖处理的小胶质细胞中。我们目前的研究重点是寻找和厚朴酚在脂多糖处理的小胶质细胞中抗炎活性的分子机制，重点是 Klf4 的调节。对于体外研究，小鼠小胶质细胞 BV-2 细胞系以及原代小胶质细胞用 500 ng/mL 脂多糖以及 1 μM 和 10 μM 和厚朴酚处理。我们在 pcDNA3.1 表达载体中克隆了全长 Klf4 cDNA，并使用 lipofectamine 将此构建体转染 BV-2 细胞进行过表达研究。对于体内研究，从用 5 mg/kg 体重的脂多糖（含或不含 2.5 或 5 mg/kg 体重的和厚朴酚）治疗的 BALB/c 小鼠中分离出脑组织。使用免疫印迹法测量 Klf4、环氧合酶-2、诱导型一氧化氮合酶和磷酸核因子-κ B 的表达。我们还测量了不同条件下细胞因子、活性氧和一氧化氮的水平。我们的研究结果表明和厚朴酚可以显着下调脂多糖刺激的小胶质细胞中促炎细胞因子和炎症酶的产生。此外，和厚朴酚还能下调脂多糖诱导的这些细胞中 Klf4 和磷酸核因子 Kappa B 的上调。我们还发现 BV-2 细胞中 Klf4 的过度表达会抑制和厚朴酚的抗炎作用。和厚朴酚可能以 Klf4 依赖性方式减少活化小胶质细胞的炎症。
Neuroinflammation occurs as a result of microglial activation in response to invading micro-organisms or other inflammatory stimuli within the central nervous system. According to our earlier findings, Krüppel-like factor 4 (Klf4), a zinc finger transcription factor, is involved in microglial activation and subsequent release of proinflammatory cytokines, tumor necrosis factor alpha, macrophage chemoattractant protein-1 and interleukin-6 as well as proinflammatory enzymes, inducible nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-treated microglial cells. Our current study focuses on finding the molecular mechanism of the anti-inflammatory activities of honokiol in lipopolysaccharide-treated microglia with emphasis on the regulation of Klf4. For in vitro studies, mouse microglial BV-2 cell lines as well as primary microglia were treated with 500 ng/mL lipopolysaccharide as well as 1 μM and 10 μM of honokiol. We cloned full-length Klf4 cDNA in pcDNA3.1 expression vector and transfected BV-2 cells with this construct using lipofectamine for overexpression studies. For in vivo studies, brain tissues were isolated from BALB/c mice treated with 5 mg/kg body weight of lipopolysaccharide either with or without 2.5 or 5 mg/kg body weight of honokiol. Expression of Klf4, cyclooxygenase-2, inducible nitric oxide synthase and phospho-nuclear factor-kappa B was measured using immunoblotting. We also measured the levels of cytokines, reactive oxygen species and nitric oxide in different conditions. Our findings suggest that honokiol can substantially downregulate the production of proinflammatory cytokines and inflammatory enzymes in lipopolysaccharide-stimulated microglia. In addition, honokiol downregulates lipopolysaccharide-induced upregulation of both Klf4 and phospho-nuclear factor-kappa B in these cells. We also found that overexpression of Klf4 in BV-2 cells suppresses the anti-inflammatory action of honokiol. Honokiol potentially reduces inflammation in activated microglia in a Klf4-dependent manner.
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DOI：
10.1152/ajpregu.1996.271.4.r990
发表时间：
1996-10-01
影响因子：
2.8
作者：
Iadecola, C;Zhang, FY
通讯作者：
Zhang, FY
影响因子：
3.7
作者：
Li, Jie;Shao, Xueting;Yao, Hangping
通讯作者：
Yao, Hangping
影响因子：
9.3
作者：
Kaushik DK;Gupta M;Das S;Basu A
通讯作者：
Basu A
影响因子：
15.9
作者：
Kreutzberg, GW
通讯作者：
Kreutzberg, GW
DOI：
10.2165/00129785-200404050-00005
发表时间：
2004-01-01
期刊：
American journal of pharmacogenomics : genomics-related research in drug development and clinical practice
影响因子：
--
作者：
Carson, Monica J;Thrash, J Cameron;Lo, David
通讯作者：
Lo, David