Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Br J Pharmacol. 2011 Nov;164(6):1661-71. doi: 10.1111/j.1476-5381.2011.01465.x.
Dissociating anti-inflammatory efficacy from the metabolic side effects of glucocorticoids is an attractive therapeutic goal. 5α-Tetrahydro-corticosterone (5αTHB), produced from corticosterone by 5α-reductases, activates glucocorticoid receptors. This study compares the effects of 5αTHB on inflammation and metabolism in vitro and in vivo.
Suppression of cytokine release by 5αTHB and corticosterone were studied following LPS activation of mouse bone marrow derived macrophages. In vivo the efficacy of these steroids to dysregulate metabolic homeostasis and modulate immune suppression and the responses to thioglycollate-induced peritonitis in C57BL/6 mice were studied following acute injection (1.5-15 mg) and chronic infusion (50 µg·day(-1) , 14 days).
In macrophages, 5αTHB increased secretion of IL-10 similarly to corticosterone (180%, 340%; data are % vehicle, treated with 5αTHB and corticosterone, respectively) and suppressed LPS-induced secretion of TNF-α (21.9%, 74.2%) and IL-6 (16.4%, 69.4%). In mice with thioglycollate-induced peritonitis, both 5αTHB and corticosterone reduced the numbers of neutrophils (58.6%, 49.9%) and inflammatory monocytes (69.5%, 96.4%), and also suppressed MCP-1 (48.7%, 80.9%) and IL-6 (53.5%, 86.7%) in peritoneal exudate. In mice chronically infused with 5αTHB and corticosterone LPS-induced production of TNF-α from whole blood was suppressed to the same degree (63.2%, 37.2%). However, in contrast to corticosterone, 5αTHB did not induce body weight loss, increase blood pressure or induce hyperinsulinaemia.
5αTHB has anti-inflammatory effects in vitro and in vivo. At doses with equivalent anti-inflammatory efficacy to corticosterone, 5αTHB did not induce metabolic toxicity and thus may be a prototype for a safer anti-inflammatory drug.
将糖皮质激素的抗炎疗效与代谢副作用区分开来是一个有吸引力的治疗目标。5α-四氢皮质酮（5αTHB）由 5α-还原酶从皮质酮产生，可激活糖皮质激素受体。本研究比较了 5αTHB 在体外和体内对炎症和代谢的影响。
通过 LPS 激活小鼠骨髓来源的巨噬细胞，研究 5αTHB 和皮质酮对细胞因子释放的抑制作用。在体内，研究这些类固醇在急性注射（1.5-15mg）和慢性输注（50μg·天(-1)，14 天）后调节代谢稳态、调节免疫抑制以及对硫代乙醇酸盐诱导的腹膜炎反应的疗效。
在巨噬细胞中，5αTHB 增加 IL-10 的分泌与皮质酮相似（180%，340%；数据分别为%载体，用 5αTHB 和皮质酮处理），并抑制 LPS 诱导的 TNF-α（21.9%，74.2%）和 IL-6（16.4%，69.4%）的分泌。在硫代乙醇酸盐诱导的腹膜炎小鼠中，5αTHB 和皮质酮均减少中性粒细胞（58.6%，49.9%）和炎症性单核细胞（69.5%，96.4%）的数量，也抑制 MCP-1（48.7%，80.9%）和 IL-6（53.5%，86.7%）在腹腔渗出液中的产生。在接受 5αTHB 和皮质酮慢性输注的小鼠中，LPS 诱导的全血 TNF-α的产生被抑制到相同程度（63.2%，37.2%）。然而，与皮质酮不同，5αTHB 不会导致体重减轻、血压升高或引起高胰岛素血症。
5αTHB 在体外和体内均具有抗炎作用。在与皮质酮等效的抗炎疗效剂量下，5αTHB 不会引起代谢毒性，因此可能是一种更安全的抗炎药物原型。
