Chapman Karen E, Coutinho Agnes, Gray Mohini, Gilmour James S, Savill John S, Seckl Jonathan R
Endocrinology Unit, Centre for Cardiovascular Sciences, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
Ann N Y Acad Sci. 2006 Nov;1088:265-73. doi: 10.1196/annals.1366.030.
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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-HSD oxoreductase but not dehydrogenase activity in cells elicited rapidly in the peritoneum by a single thioglycollate injection. 11beta-HSD oxoreductase activity remained high in peritoneal cells until the inflammation resolved. In vitro, the 11beta-HSD1 substrate, 11-dehydrocorticosterone, increased macrophage phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11beta-HSD1: these cells solely expressed the type 1 11beta-HSD isozyme (not 11beta-HSD2), and carbenoxolone, an 11beta-HSD inhibitor, prevented the increase in phagocytosis elicited by 11-dehydrocorticosterone. Macrophages from 11beta-HSD1-deficient mice failed to respond to 11-dehydrocorticosterone. In vivo, 11beta-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, 11beta-HSD1-deficient mice exhibited delayed resolution of inflammation in experimental arthritis. These findings suggest 11beta-HSD1 may be a component of mechanisms engaged early during the inflammatory response that promote its subsequent resolution.
糖皮质激素被广泛用于治疗包括类风湿性关节炎在内的慢性炎症性疾病。它们促进对炎症正常消退很重要的机制，尤其是巨噬细胞对正在经历凋亡的白细胞的吞噬作用。11β-羟基类固醇脱氢酶1型（11β-HSD1）对糖皮质激素的受体前代谢通过将细胞内原本无活性的可的松（在人类中为11-脱氢皮质酮，在小鼠中为皮质酮）氧化还原为活性皮质醇（在小鼠中为皮质酮）来放大细胞内糖皮质激素水平，这些细胞表达该酶。最近，我们在急性炎症小鼠模型中发现，单次注射巯基乙酸盐后，腹膜中快速诱导的细胞中11β-HSD氧化还原酶表达高，但脱氢酶活性不高。在炎症消退之前，腹膜细胞中的11β-HSD氧化还原酶活性一直很高。在体外，11β-HSD1底物11-脱氢皮质酮与皮质酮一样，能同等程度地增加巨噬细胞对凋亡中性粒细胞的吞噬作用。这种作用依赖于11β-HSD1：这些细胞仅表达1型11β-HSD同工酶（而非11β-HSD2），11β-HSD抑制剂甘草次酸可阻止11-脱氢皮质酮引起的吞噬作用增加。来自11β-HSD1缺陷小鼠的巨噬细胞对11-脱氢皮质酮无反应。在体内，11β-HSD1缺陷小鼠在无菌性腹膜炎期间巨噬细胞吞噬能力的获得出现延迟，且游离凋亡中性粒细胞数量增加。重要的是，在初步实验中，11β-HSD1缺陷小鼠在实验性关节炎中炎症消退延迟。这些发现表明，11β-HSD1可能是炎症反应早期参与促进其后续消退的机制的一个组成部分。
