Amano Y, Lee S W, Allison A C
Syntex Research, Palo Alto, California 94304.
Mol Pharmacol. 1993 Feb;43(2):176-82.
The mechanism by which glucocorticoids inhibit interleukin (IL)-1 and IL-6 formation in human monocytes and a promonocytic cell line activated by Escherichia coli lipopolysaccharide was analyzed. Dexamethasone (DEX) decreased levels of IL-1 alpha and IL-1 beta mRNAs in a dose-related fashion. The DEX-induced decrease in levels of IL-1 alpha and IL-1 beta mRNAs was abolished by the steroid receptor antagonist RU486. The levels of IL-1 alpha and IL-1 beta proteins within the cells and of IL-1 beta in the culture medium were decreased by DEX to comparable extents, so that DEX had no detectable effect on cytokine secretion. DEX did not influence lipopolysaccharide-induced transcription of the IL-1 beta gene in monocytes. However, DEX markedly decreased the stability of IL-1 beta mRNA, as shown both by steady state measurements and by pulse-labeling. DEX-induced instability of IL-1 beta mRNA required protein synthesis. DEX was also found to be a potent inhibitor of IL-1-induced expression of the IL-6 gene in connective tissue-type cells from the synovium of patients with rheumatoid arthritis. Inhibition of the formation of proinflammatory cytokines, including IL-1 beta and tumor necrosis factor-alpha, is a mechanism by which glucocorticoids exert anti-inflammatory effects. Inhibition by glucocorticoids of the expression of IL-1 alpha in antigen-presenting cells could decrease the capacity of the cells to stimulate the proliferation of T lymphocytes. This activity, as well as inhibition of the production and effects of IL-1 beta, including induced formation of IL-6 and of certain lymphokines, could explain the immunosuppressive effects of glucocorticoids.
分析了糖皮质激素抑制人单核细胞和由大肠杆菌脂多糖激活的前单核细胞系中白细胞介素（IL）-1和IL-6形成的机制。地塞米松（DEX）以剂量相关的方式降低IL-1α和IL-1βmRNA的水平。类固醇受体拮抗剂RU486消除了DEX诱导的IL-1α和IL-1βmRNA水平的降低。DEX使细胞内IL-1α和IL-1β蛋白以及培养基中IL-1β的水平降低到相当程度，因此DEX对细胞因子分泌没有可检测到的影响。DEX不影响脂多糖诱导的单核细胞中IL-1β基因的转录。然而，如稳态测量和脉冲标记所示，DEX显著降低了IL-1βmRNA的稳定性。DEX诱导的IL-1βmRNA不稳定性需要蛋白质合成。还发现DEX是类风湿性关节炎患者滑膜结缔组织型细胞中IL-1诱导的IL-6基因表达的有效抑制剂。抑制包括IL-1β和肿瘤坏死因子-α在内的促炎细胞因子的形成是糖皮质激素发挥抗炎作用的一种机制。糖皮质激素对抗抗原呈递细胞中IL-1α表达的抑制作用可能会降低细胞刺激T淋巴细胞增殖的能力。这种活性以及对IL-1β的产生和作用的抑制，包括诱导IL-6和某些淋巴因子的形成，可以解释糖皮质激素的免疫抑制作用。
