Carbon monoxide orchestrates a protective response through PPARγ
Carbon monoxide orchestrates a protective response through PPARγ
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DOI：
10.1016/j.immuni.2006.03.012
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发表时间：
2006-05-01
期刊：
影响因子：
32.4
通讯作者：
Otterbein, Leo E.
中科院分区：
文献类型：
--
作者：
Bilban, Martin;Bach, Fritz H.;Otterbein, Leo E.
一氧化碳 (CO) 抑制巨噬细胞对 LPS 的促炎反应。我们假设 CO 通过诱导一种或多种分子来抑制随后应激的炎症反应。巨噬细胞在体外单独接触 CO 会产生短暂的线粒体衍生 ROS 爆发，从而导致 PPAR γ 的表达。 PPAR γ 表达被证明对于介导 CO 的抗炎作用至关重要。阻断 CO 介导的 ROS 生成增加可以防止 PPAR γ 诱导，而阻断 PPAR γ 则可以防止 CO 的抗炎作用。在小鼠急性肺损伤模型中，CO 阻断 Egr-1（炎症的核心介质）的表达，并减少组织损伤；抑制 PPAR γ 可消除这两种效应。这些数据将线粒体氧化酶确定为 CO 的（也许是）初始细胞靶标，并证明 CO 通过线粒体上调 PPAR γ 的表达，这确保随后的应激刺激将导致细胞保护而不是促炎表型。
Carbon monoxide (CO) suppresses proinflammatory responses in macrophages reacting to LPS. We hypothesize that CO acts by inducing a molecule(s) that suppresses the inflammatory response to subsequent stress. Exposure of macrophages to CO alone in vitro produced a brief burst of mitochondrial-derived ROS, which led to expression of PPAR gamma. PPAR gamma expression proved essential for mediating the antiinflammatory effects of CO. Blocking the CO-mediated increase in ROS generation prevented PPAR gamma induction, and blocking PPAR gamma prevented CO's anti-inflammatory effects. In a model of acute lung injury in mice, CO blocked expression of Egr-1, a central mediator of inflammation, and decreased tissue damage; inhibition of PPAR gamma abrogated both effects. These data identify the mitochondrial oxidases as an (perhaps the) initial cellular target of CO and demonstrate that CO upregulates expression of PPAR gamma via the mitochondria, which assures that a subsequent stress stimulus will lead to a cytoprotective as opposed to a proinflammatory phenotype.