Institute of Molecular Systems Biomedicine, China Medical University, Taichung, Taiwan 40402, R.O.C.
J Nutr Biochem. 2010 Dec;21(12):1186-92. doi: 10.1016/j.jnutbio.2009.10.004. Epub 2010 Feb 9.
Macrophage motility is vital in innate immunity. Lipopolysaccharide (LPS)-mediated macrophage migration requires the enhancement of Src expression and enzymatic activity, which can be regulated by inducible nitric oxide synthase (iNOS). As a major short-chain fatty acid with histone deacetylase (HDAC) inhibitor activity, butyrate exerts anti-inflammatory effect by regulating the expression of cytokines. However, the influence of butyrate on macrophage movement was vague. In this study, we observed that butyrate inhibited migration of both RAW264.7 and rat peritoneal macrophages elicited by LPS. Unlike its myeloid relatives (i.e. Lyn, Fgr and Hck) whose expression was almost unaltered in the presence or absence of butyrate in LPS-treated macrophages, LPS-mediated Src induction was greatly suppressed by butyrate and that could be attributable to reduced level of the src transcript. Similar phenomenon was also detected in LPS-treated macrophages exposed to another HDAC inhibitor, trichostatin A (TSA). Consistent with the indispensability of iNOS in promoting macrophage mobilization via Src up-regulation and the activation of both Src and FAK, we did observe concomitant decrement of iNOS, Src and the suppressed activity of Src and FAK in butyrate- or TSA-pretreated macrophages following LPS exposure. These results imply that by virtue of reduction of Src, butyrate could effectively hamper LPS-triggered macrophage locomotion.
巨噬细胞的迁移能力对先天免疫至关重要。脂多糖 (LPS) 介导的巨噬细胞迁移需要增强Src 的表达和酶活性，这可以通过诱导型一氧化氮合酶 (iNOS) 来调节。丁酸盐作为一种主要的短链脂肪酸，具有组蛋白去乙酰化酶 (HDAC) 抑制剂活性，通过调节细胞因子的表达发挥抗炎作用。然而，丁酸盐对巨噬细胞运动的影响尚不清楚。在本研究中，我们观察到丁酸钠抑制 LPS 诱导的 RAW264.7 细胞和大鼠腹腔巨噬细胞的迁移。与髓样细胞（即 Lyn、Fgr 和 Hck）不同，在 LPS 处理的巨噬细胞中，丁酸钠的存在或不存在几乎不会改变其表达，而 LPS 诱导的Src 诱导则被丁酸钠大大抑制，这可能归因于 src 转录本水平降低。在 LPS 处理的巨噬细胞中暴露于另一种 HDAC 抑制剂曲古抑菌素 A (TSA) 时，也观察到类似的现象。与 iNOS 通过上调 Src 并激活 Src 和 FAK 促进巨噬细胞动员的必要性一致，我们确实观察到在 LPS 暴露后，丁酸钠或 TSA 预处理的巨噬细胞中 iNOS、Src 和 Src 和 FAK 活性的抑制伴随著协同减少。这些结果表明，通过降低 Src，丁酸钠可以有效地阻止 LPS 触发的巨噬细胞迁移。
