Novel anti-inflammatory mechanisms of the Glucocorticoid Receptor

糖皮质激素（GC）是一种有效的抗炎药物，广泛应用于治疗。然而，由于GC治疗过程中经常发生的分解代谢副作用，它们的作用受到限制。它们严重损害了患者的生活质量，并造成数亿美元的额外治疗费用。因此，了解GC发挥其抗炎和分解代谢作用的分子机制，对于开发新的更有针对性的药物和治疗方法具有重要意义。目前学界公认的观点认为，GC的抗炎作用机制不依赖于糖皮质激素受体（GR）的DNA结合，而其副作用则被认为是由二聚化依赖性DNA结合介导的。然而，在未发表的研究中，我们发现在小鼠接触性过敏和脓毒症模型中，GC的免疫抑制活性需要GR的DNA结合。缺乏二聚化诱导的GR DNA结合功能的小鼠（GRdim小鼠）在这些疾病范式中对GC没有反应。通过对GRdim小鼠巨噬细胞的表达谱分析和RT-PCR分析，我们发现野生型巨噬细胞受GC调控的基因，而GRdim细胞不受GC调控。这些基因被认为是介导抗炎作用机制的候选者。我们打算通过细胞培养试验、疾病模型组织和这些疾病的体内模型来分析这些GC调节基因的功能。我们计划进一步研究二聚化GR在启动子及其相互作用因子的背景下对这些基因的调控。因此，我们希望确定参与GC功能的新途径。这可能会导致改进治疗的新模型，并确定新的抗炎药物靶点。

Glucocorticoid hormones (GC) are potent anti-inflammatory agents, which are widely used in therapy. However, their usefulness is limited by catabolic side effects that often occur during GC treatment. They strongly compromise the quality of life of the patients and cause additional treatment costs in the order of hundreds of million ¿. It is therefore of great importance to understand the molecular mechanisms by which GC exert their anti-inflammatory as well as their catabolic action in order to develop new and more specific drugs and treatments. The currently accepted view in the field attributes the anti-inflammatory action of GC to mechanisms which do not depend on DNA binding by the glucocorticoid receptor (GR), whereas side effect are believed to be mediated by dimerization-dependent DNA-binding. However, in unpublished studies we showed that in murine models for contact allergy and sepsis, DNA binding of the GR is required for the immune suppressive activity of GC. Mice lacking the dimerization-induced DNA binding function of the GR (GRdim mice) do not react to GC in these disease paradigms. By expression profiling and RT-PCR analysis of macrophages derived from GRdim mice, we identified genes that are regulated by GC in wild type, but not in GRdim cells. These genes are putative candidates for the mechanisms involved in mediating GCinduced anti-inflammatory action. We intend to analyze the function of these GC modulated genes by cell culture assays, in tissues of disease models and in in vivo models of these diseases. We further plan to study the regulation of these genes by the dimerizing GR in the context of their promoters, and of interacting factors that are required for this regulation. We hope to thus identify novel pathways involved in GC function. This could lead to new models for improved therapies and to the identification of novel anti-inflammatory drug targets.