Almawi W Y, Saouda M S, Stevens A C, Lipman M L, Barth C M, Strom T B
Department of Biochemistry, Faculty of Medicine, American University of Beirut, Lebanon.
J Immunol. 1996 Dec 15;157(12):5231-9.
The glucocorticoids (GCs) dexamethasone (DEX) and prednisolone (PRED), in a concentration-dependent fashion, profoundly inhibit mitogen-induced proliferation of human peripheral blood mononuclear lymphocytes (PBML). This inhibition was specific for GCs, as non-GC steroids were devoid of any antiproliferative capacity. GCs enhanced the mRNA (Northern blot) and protein (Western blot) expression of the calcium and phospholipid binding proteins lipocortin I, II, and V. As a consequence of mitogenic stimulation, PBML secrete PGE2 and leukotriene B4 (LTB4). Antiproliferative concentrations of both DEX and PRED as well as recombinant lipocortin I abolished PGE2 and LTB4 production, suggesting an involvement of lipocortins in GC-mediated antiproliferative effects, possibly by inhibiting eicosanoid production and, consequently, mitogen-induced cellular proliferation. Whereas 5,8,11,14-eicosatetraynoic acid and nordihydroguaiaretic acid mimicked DEX and PRED in inhibiting PGE2 and LTB4 production, neither 5,8,11,14-eicosatetraynoic acid nor nordihydroguaiaretic acid had any effect on mitogen-induced PBML proliferation, indicating that the GC-mediated antiproliferative effect is separate from their effects on eicosanoid release. Furthermore, neutralizing anti-lipocortin I and anti-lipocortin II mAb, while reversing the inhibitory activity of DEX and PRED on PGE2 and LTB4 production, only partially reversed DEX- and PRED-mediated antiproliferative effects. This indicates that the GC-mediated antiproliferative effect is not dependent on inhibition of eicosanoid release by lipocortins and suggests the existence of lipocortin-dependent and lipocortin-independent pathways by which GCs mediate their antiproliferative effects.
糖皮质激素（GCs）地塞米松（DEX）和泼尼松龙（PRED）以浓度依赖的方式，显著抑制有丝分裂原诱导的人外周血单个核细胞（PBML）增殖。这种抑制作用对GCs具有特异性，因为非GC类固醇没有任何抗增殖能力。GCs增强了钙和磷脂结合蛋白脂皮质素I、II和V的mRNA（Northern印迹法）和蛋白（Western印迹法）表达。作为有丝分裂原刺激的结果，PBML分泌前列腺素E2（PGE2）和白三烯B4（LTB4）。DEX和PRED的抗增殖浓度以及重组脂皮质素I均消除了PGE2和LTB4的产生，这表明脂皮质素可能参与了GC介导的抗增殖作用，可能是通过抑制类花生酸的产生，进而抑制有丝分裂原诱导的细胞增殖。虽然5,8,11,14-二十碳四烯酸和去甲二氢愈创木酸在抑制PGE2和LTB4产生方面模拟了DEX和PRED，但5,8,11,14-二十碳四烯酸和去甲二氢愈创木酸对有丝分裂原诱导的PBML增殖均无任何影响，这表明GC介导的抗增殖作用与其对类花生酸释放的影响是分开的。此外，中和抗脂皮质素I和抗脂皮质素II单克隆抗体，虽然逆转了DEX和PRED对PGE2和LTB4产生的抑制活性，但仅部分逆转了DEX和PRED介导的抗增殖作用。这表明GC介导的抗增殖作用不依赖于脂皮质素对类花生酸释放的抑制，并提示存在脂皮质素依赖性和脂皮质素非依赖性途径，通过这些途径GCs介导其抗增殖作用。
