Scheinman R I, Cogswell P C, Lofquist A K, Baldwin A S
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, USA.
Science. 1995 Oct 13;270(5234):283-6. doi: 10.1126/science.270.5234.283.
Glucocorticoids are potent immunosuppressive drugs, but their mechanism is poorly understood. Nuclear factor kappa B (NF-kappa B), a regulator of immune system and inflammation genes, may be a target for glucocorticoid-mediated immunosuppression. The activation of NF-kappa B involves the targeted degradation of its cytoplasmic inhibitor, I kappa B alpha, and the translocation of NF-kappa B to the nucleus. Here it is shown that the synthetic glucocorticoid dexamethasone induces the transcription of the I kappa B alpha gene, which results in an increased rate of I kappa B alpha protein synthesis. Stimulation by tumor necrosis factor causes the release of NF-kappa B from I kappa B alpha. However, in the presence of dexamethasone this newly released NF-kappa B quickly reassociates with newly synthesized I kappa B alpha, thus markedly reducing the amount of NF-kappa B that translocates to the nucleus. This decrease in nuclear NF-kappa B is predicted to markedly decrease cytokine secretion and thus effectively block the activation of the immune system.
糖皮质激素是强效免疫抑制药物，但其作用机制尚不清楚。核因子κB（NF-κB）作为免疫系统和炎症相关基因的调节因子，可能是糖皮质激素介导免疫抑制的靶点。NF-κB的激活涉及胞质抑制因子IκBα的靶向降解以及NF-κB向细胞核的转位。本文表明，合成糖皮质激素地塞米松可诱导IκBα基因转录，导致IκBα蛋白合成速率增加。肿瘤坏死因子刺激可使NF-κB从IκBα中释放出来。然而，在地塞米松存在的情况下，新释放的NF-κB会迅速与新合成的IκBα重新结合，从而显著减少转位至细胞核的NF-κB数量。预计细胞核内NF-κB的减少将显著降低细胞因子分泌，从而有效阻断免疫系统的激活。
