Yamada T, Murayama T, Nomura Y
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
J Neuroimmunol. 1998 Jan;81(1-2):14-9. doi: 10.1016/s0165-5728(97)00141-0.
Glucocorticoids (GC) are known to inhibit the mitogen-induced proliferation of T cells. Some of the effects of GC have been ascribed to the inhibition of nitrogen monoxide (NO) production, since NO is involved in the effecter function of phagocytic cells. Although the effects of GC in vitro on thymocytes are known, the effect of in vivo GC treatment on proliferation and NO synthesis in thymocytes has not been clarified. In this study, we investigated the effects of the administration of hydrocortisone succinate (HC), a potent anti-inflammatory GC, in Sprague-Dawley rats by s.c. injection (100 mg/kg). A substantial reduction of concanavalin A (Con A)-stimulated [3H]thymidine incorporation was observed in the thymocytes from HC-treated rats. This effect was accompanied by an increase in the Con A-stimulated expression of the inducible type of nitric oxide synthase (iNOS) and nitrite accumulation. The constitutive type of NOS (cNOS) in thymocytes did not change during the course of in vivo HC treatment. Addition of NO donors, which stimulated cyclic GMP accumulation, to rat thymocytes in vitro inhibited Con A-stimulated DNA synthesis. Addition of dibutyryl cyclic GMP, a membrane permeable analog, also inhibited DNA synthesis. Co-culture with N(G)monomethyl-L-arginine, an inhibitor of NOS, recovered Con A-stimulated [3H]thymidine incorporation in the thymocytes from HC-treated rats. These findings suggest that NO and cyclic GMP inhibited DNA synthesis in rat thymocytes and that HC treatment in vivo inhibited DNA synthesis via the expression of the iNOS protein, and the accumulation of NO and cyclic GMP. Although it is known that GC regulate iNOS expression negatively in several types of cells in vitro, GC treatment in vivo regulates iNOS protein expression positively in rat thymocytes.
已知糖皮质激素（GC）可抑制丝裂原诱导的T细胞增殖。GC的一些作用归因于对一氧化氮（NO）生成的抑制，因为NO参与吞噬细胞的效应功能。虽然GC在体外对胸腺细胞的作用是已知的，但体内GC治疗对胸腺细胞增殖和NO合成的影响尚未阐明。在本研究中，我们通过皮下注射（100 mg/kg）研究了强力抗炎GC琥珀酸氢化可的松（HC）对Sprague-Dawley大鼠的影响。在HC处理大鼠的胸腺细胞中观察到刀豆球蛋白A（Con A）刺激的[3H]胸苷掺入显著减少。这种效应伴随着Con A刺激的诱导型一氧化氮合酶（iNOS）表达增加和亚硝酸盐积累。在体内HC治疗过程中，胸腺细胞中的组成型NOS（cNOS）没有变化。在体外向大鼠胸腺细胞中添加刺激环鸟苷酸积累的NO供体可抑制Con A刺激的DNA合成。添加膜通透性类似物二丁酰环鸟苷酸也可抑制DNA合成。与NOS抑制剂N（G）单甲基-L-精氨酸共培养可恢复HC处理大鼠胸腺细胞中Con A刺激的[3H]胸苷掺入。这些发现表明，NO和环鸟苷酸抑制大鼠胸腺细胞中的DNA合成，并且体内HC治疗通过iNOS蛋白的表达以及NO和环鸟苷酸的积累来抑制DNA合成。虽然已知GC在体外对几种类型的细胞中iNOS表达有负调节作用，但体内GC治疗在大鼠胸腺细胞中对iNOS蛋白表达有正调节作用。
