Transcellular biosynthesis contributes to the production of leukotrienes during inflammatory responses in vivo
Transcellular biosynthesis contributes to the production of leukotrienes during inflammatory responses in vivo
复制标题
DOI：
10.1172/jci200214869
复制
发表时间：
2002-05-01
影响因子：
15.9
通讯作者：
Koller, BH
中科院分区：
文献类型：
--
作者：
Fabre, JE;Goulet, JL;Koller, BH
白三烯是一种脂质介质，通过激活存在于几乎所有细胞中的受体来引起主要的促炎反应。白三烯的产生受到严格调控，白三烯合成第一步所需的酶5-脂氧合酶的表达通常仅限于白细胞。从活化的白细胞细胞膜释放的花生四烯酸通过5-脂氧合酶迅速转化为LTA(4)。LTA(4)分别通过LTC4合成酶或LTA(4)水解酶进一步代谢为LTC4或LTB4。与5-脂氧合酶不同，这些酶在大多数组织中表达。这一观察结果表明，在某些情况下，白细胞产生的LTA(4)可能在转化为LTC4或LTB4之前被传递给其他类型的细胞。虽然体外研究表明，这一被称为跨细胞生物合成的过程可以导致白三烯的产生，但尚不可能确定这一途径在体内的意义。利用一系列由5-脂氧合酶和LTA(4)水解酶缺陷小鼠产生的骨髓嵌合体，我们在这里证明了跨细胞生物合成有助于体内白三烯的产生，并且通过这一途径产生的白三烯足以显著地促进持续炎症反应特征的生理变化。
Leukotrienes are lipid mediators that evoke primarily proinflammatory responses by activating receptors present on virtually all cells. The production of leukotrienes is tightly regulated, and expression of 5-lipoxygenase, the enzyme required for the first step in leukotriene synthesis, is generally restricted to leukocytes. Arachidonic acid released from the cell membrane of activated leukocytes is rapidly converted to LTA(4) by 5-lipoxygenase. LTA(4) is further metabolized to either LTC4 or LTB4 by the enzyme LTC4 synthase or LTA(4) hydrolase, respectively. Unlike 5-lipoxygenase, these enzymes are expressed in most tissues. This observation previously has led to the suggestion that LTA(4) produced by leukocytes may, in some cases, be delivered to other cell types before being converted into LTC4 or LTB4. While in vitro studies indicate that this process, termed transcellular biosynthesis, can lead to the production of leukotrienes, it has not been possible to determine the significance of this pathway in vivo. Using a series of bone marrow chimeras generated from 5-lipoxygenase- and LTA(4) hydrolase-deficient mice, we show here that transcellular biosynthesis contributes to the production of leukotrienes in vivo and that leukotrienes produced by this pathway are sufficient to contribute significantly to the physiological changes that characterize an ongoing inflammatory response.