ENDOGENOUS GLUCOCORTICOIDS REGULATE AN INDUCIBLE CYCLOOXYGENASE ENZYME
ENDOGENOUS GLUCOCORTICOIDS REGULATE AN INDUCIBLE CYCLOOXYGENASE ENZYME
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DOI：
10.1073/pnas.89.9.3917
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发表时间：
1992-05-01
影响因子：
11.1
通讯作者：
NEEDLEMAN, P
中科院分区：
文献类型：
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作者：
MASFERRER, JL;SEIBERT, K;NEEDLEMAN, P
通过比较内源性糖皮质激素对去肾上腺和假去肾上腺小鼠环氧化酶表达和前列腺素合成的影响，探讨内源性糖皮质激素对环氧化酶表达的影响。与假对照组相比，肾上腺切除小鼠的腹腔巨噬细胞在环加氧酶合成和活性方面表现出2至3倍的诱导作用。静脉注射亚致死剂量的内毒素（5 μ g/kg）进一步刺激环加氧酶合成，导致前列腺素产量增加4倍。从正常小鼠获得的巨噬细胞中也可以实现类似的环加氧酶诱导，但只有在高剂量的内毒素（2.5 mg/kg）对肾上腺切除小鼠100%致死后才能实现。地塞米松恢复肾上腺切除动物的糖皮质激素完全抑制环加氧酶升高，保护这些动物免受内毒素引起的死亡。相比之下，在肾上腺切除小鼠的肾脏中没有观察到环加氧酶诱导的迹象，即使用内毒素处理。地塞米松不影响正常肾和去肾上腺肾的环氧化酶活性和前列腺素的产生。这些数据表明存在一种组成型环加氧酶，它通常存在于大多数细胞和组织中，不受类固醇的影响；存在一种诱导型环加氧酶，它仅在炎症背景下由促炎细胞（如巨噬细胞）表达，并受糖皮质激素调节。在正常生理条件下，糖皮质激素维持对诱导型环氧合酶表达的强直性抑制。糖皮质激素的消耗或内毒素等炎症刺激的存在会导致这种酶的快速诱导，导致炎症反应加剧，通常是致命的。
The effect of endogenous glucocorticoids on the expression of the cyclooxygenase enzyme was studied by contrasting cyclooxygenase expression and prostanoid synthesis in adrenalectomized and sham-adrenalectomized mice with or without the concurrent administration of endotoxin. Peritoneal macrophages obtained from adrenalectomized mice showed a 2- to 3-fold induction in cyclooxygenase synthesis and activity when compared to sham controls. Intravenous injection of a sublethal dose of endotoxin (5-mu-g/kg) further stimulated cyclooxygenase synthesis, resulting in a 4-fold increase in prostaglandin production. Similar cyclooxygenase induction can be achieved in macrophages obtained from normal mice but only after high doses of endotoxin (2.5 mg/kg) that are 100% lethal to adrenalectomized mice. Restoration of glucocorticoids in adrenalectomized animals with dexamethasone completely inhibited the elevated cyclooxygenase and protected these animals from endotoxin-induced death. In contrast, no signs of cyclooxygenase induction were observed in the kidneys of the adrenalectomized mice, even when treated with endotoxin. Dexamethasone did not affect the constitutive cyclooxygenase activity and prostaglandin production present in normal and adrenalectomized kidneys. These data indicate the existence of a constitutive cyclooxygenase that is normally present in most cells and tissues and is unaffected by steroids and of an inducible cyclooxygenase that is expressed only in the context of inflammation by proinflammatory cells, like macrophages, and that is under glucocorticoid regulation. Under normal physiological conditions glucocorticoids maintain tonic inhibition of inducible cyclooxygenase expression. Depletion of glucocorticoids or the presence of an inflammatory stimulus such as endotoxin causes rapid induction of this enzyme, resulting in an exacerbated inflammatory response that is often lethal.