Novel anti-inflammatory mechanisms of the Glucocorticoid Receptor

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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 However, in unpublished studies we showed that in murine models for contact allergy and sepsis, DNA binding of the GR is required for the immune suppressive activity of GC.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.