Role of Transcriptional Activation of IκBα in Mediation of Immunosuppression by Glucocorticoids

作者：Robert I. Scheinman, Patricia C. Cogswell, Alan K. Lofquist, Albert S. Baldwin · 发表于：Science · 年份：1995 · DOI：10.1126/science.270.5234.283 · 被引用次数：1725 · 研究领域：NF-κB Signaling Pathways、Immune Response and Inflammation、Estrogen and related hormone effects

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.