Oyanagui Y
2nd Pharmacology, Drug Development Laboratories I, Fujisawa Pharmaceutical Co., Kashima, Osaka, Japan.
Eur J Pharmacol. 1998 Mar 5;344(2-3):241-9. doi: 10.1016/s0014-2999(97)01561-6.
A possible new common action of immunosuppressants, besides suppression of the genes for cytokines like interleukin-2, was investigated in in vivo models. Dexamethasone (0.1 mg/kg, s.c.) failed to suppress ischemic paw edema in mice 1 h after its injection, but maximal suppression was achieved at 3 h (20%) whereafter the suppression decreased at 6 and 18 h (11% and 10%). Pretreatment with oral FK506 (chemical name is recently donated as tacrolimus, 0.1 mg/kg) resulted in 38%, 52%, 23% and 17% suppression at 1, 3, 6 and 18 h, respectively. Cyclosporin A (1 mg/kg), rapamycin (0.1 mg/kg) and deoxyspergualin (1 mg/kg) showed a similar pattern of suppressions after dexamethasone. Transforming growth factor-beta1 (TGF-beta1, 0.3 microg/kg, i.p.) maintained the suppression elicited by an immunosuppressant (42-58%) at 6 h after dexamethasone, whereas transforming growth factor-beta1 and/or an immunosuppressant were not suppressive. Suppression, irrespective of the agent that elicited it, was blocked by nitric oxide (NO) synthase inhibitor, anti-oxidant enzymes and cycloheximide. Endogenous nitric oxide or oxyradicals are essential for the action of dexamethasone in vivo. The four immunosuppressants bound to specific heat-hock proteins (hsp) in the glucocorticoid receptor complex and might enhance the synthesis of anti-inflammatory protein(s).
除了抑制白细胞介素 - 2等细胞因子的基因外，免疫抑制剂可能存在的一种新的共同作用在体内模型中进行了研究。地塞米松（0.1mg/kg，皮下注射）在注射后1小时未能抑制小鼠缺血性爪肿胀，但在3小时达到最大抑制（20%），此后在6小时和18小时抑制作用减弱（分别为11%和10%）。口服FK506（化学名称最近改为他克莫司，0.1mg/kg）预处理在1、3、6和18小时分别导致38%、52%、23%和17%的抑制。环孢素A（1mg/kg）、雷帕霉素（0.1mg/kg）和去氧精胍菌素（1mg/kg）在地塞米松处理后表现出类似的抑制模式。转化生长因子 - β1（TGF - β1，0.3μg/kg，腹腔注射）在地塞米松处理后6小时维持免疫抑制剂引起的抑制作用（42 - 58%），而转化生长因子 - β1和/或免疫抑制剂本身无抑制作用。无论由何种药物引起，抑制作用均被一氧化氮（NO）合酶抑制剂、抗氧化酶和环己酰亚胺阻断。内源性一氧化氮或氧自由基对地塞米松在体内的作用至关重要。这四种免疫抑制剂与糖皮质激素受体复合物中的特定热休克蛋白（hsp）结合，可能增强抗炎蛋白的合成。
