Local amplification of Glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 and its role in the inflammatory response
Local amplification of Glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 and its role in the inflammatory response
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DOI：
10.1196/annals.1366.030
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
Seckl, Jonathan R.
中科院分区：
文献类型：
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作者：
Chapman, Karen E.;Coutinho, Agnes;Seckl, Jonathan R.
糖皮质激素广泛用于治疗慢性炎症性疾病，包括类风湿性关节炎。它们促进炎症正常消退的重要机制，特别是巨噬细胞吞噬经历凋亡的白细胞。糖皮质激素通过11 β-羟基类固醇脱氢酶1型（11 β-HSD 1）的受体前代谢通过在表达酶的细胞内将固有惰性的可的松（在人类中，在小鼠中为11-脱氢皮质酮）氧化还原为活性皮质醇（在小鼠中为皮质酮）来放大糖皮质激素的细胞内水平。最近，我们在小鼠急性炎症模型中显示，通过单次巯基乙酸盐注射在腹膜中迅速引起细胞中11 β-HSD氧化还原酶的高表达，但不引起脱氢酶活性。11 β-HSD氧化还原酶活性在腹膜细胞中保持高水平，直到炎症消退。在体外，11 β-HSD 1底物11-脱氢皮质酮增加巨噬细胞对凋亡中性粒细胞的吞噬作用，其程度与皮质酮相同。这种作用依赖于11 β-HSD 1：这些细胞只表达1型11 β-HSD同工酶（而不是11 β-HSD 2），而甘珀酸（一种11 β-HSD抑制剂）阻止了由11-脱氢皮质酮引起的吞噬作用的增加。来自11 β-HSD 1缺陷小鼠的巨噬细胞对11-脱氢皮质酮没有反应。在体内，11个β-HSD 1缺陷小鼠表现出巨噬细胞吞噬能力的获得延迟，并且在无菌性腹膜炎期间游离凋亡中性粒细胞的数量增加。重要的是，在初步实验中，11只β-HSD 1缺陷小鼠在实验性关节炎中表现出炎症消退延迟。这些发现表明，11 β-HSD 1可能是炎症反应早期参与的机制的一个组成部分，促进其随后的解决。
Glucocorticoids are widely used to treat chronic inflammatory conditions including rheumatoid arthritis. They promote mechanisms important for normal resolution of inflammation, notably macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) amplifies intracellular levels of glucocorticoids by oxoreduction of intrinsically inert cortisone (in humans, 11-dehydrocorticosterone in mice) into active cortisol (corticosterone in mice) within cells expressing the enzyme. Recently, we have shown in a mouse model of acute inflammation, high expression of 11 beta-HSD oxoreductase but not dehydrogenase activity in cells elicited rapidly in the peritoneum by a single thioglycollate injection. 11 beta-HSD oxoreductase activity remained high in peritoneal cells until the inflammation resolved. In vitro, the 11 beta-HSD1 substrate, 11-dehydrocorticosterone, increased macrophage phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11 beta-HSD1: these cells solely expressed the type 1 11 beta-HSD isozyme (not 11 beta-HSD2), and carbenoxolone, an 11 beta-HSD inhibitor, prevented the increase in phagocytosis elicited by 11-dehydrocorticosterone. Macrophages from 11 beta-HSD1-deficient mice failed to respond to 11-dehydrocorticosterone. In vivo, 11 beta-HSD1-deficient mice showed a delay in acquisition of macrophage phagocytic competence and had an increased number of free apoptotic neutrophils during sterile peritonitis. Importantly, in preliminary experiments, 11 beta-HSD1-deficient mice exhibited delayed resolution of inflammation in experimental arthritis. These findings suggest 11 beta-HSD1 may be a component of mechanisms engaged early during the inflammatory response that promote its subsequent resolution.