Translation of abstract (English)
The innate immune response is triggered by bacterial activators such as lipopolysaccharide (LPS). This leads to production of mediators which co-ordinate the body's response to inflammation. In addition to the beneficial effects of such a response to LPS, this activation also accounts for the pathophysiologic state. To suppress the ongoing inflammation, several glucocorticoid-based drugs have been used. Their efficacy is based upon their ability to activate the glucocorticoid receptor (GR) which in turns predominantly mediates transrepression of target genes. A combination of array-based technologies and subtractive suppressive hybridisation has allowed for the identification of genes that are altered upon activation of peritoneal macrophages by LPS, and those whose expression is further modulated upon administration of glucocorticoids (GC). In total, more than 350 genes/ESTs were identified as being induced or repressed by LPS, whereas 106 (30) of them responded to GC treatment. The molecular mechanisms of GC action on the expression of LPS induced or repressed genes have been deciphered using peritoneal macrophages obtained from GRdim and GRLysCre mutant mice. GRdim mice carry a dimerisation-defective GR in which the receptor is no longer able to dimerise and bind to its response elements whereas GR interactions with other transcription factors, which are independent of binding to DNA, are preserved. Only a small subset of all GC-regulated genes in peritoneal macrophages (12 out of 106) were identified as being modulated by GCs in GRdim cells, in contrast to the expression of 94 (89) of GC-responsive genes/ESTs. . Gene expression profiling of PMF from GRLysCre mice, mutant mice which lack the GR in cells of the myeloid lineage, confirmed the GR-specificity of GC action, since induction or repression of target genes by GCs was abolished in these cells.
|Supervisor:||Schütz, Prof. Dr. Günther|
|Date of thesis defense:||16 July 2002|
|Faculties / Institutes:||Service facilities > German Cancer Research Center (DKFZ)|
|Subjects:||570 Life sciences|
|Controlled Keywords:||Glukokortikoidrezeptor, Makrophage, Genexpression, Entzündung|
|Uncontrolled Keywords:||Glucocorticoid receptor , Macrophages , Gene expression profiling , Inflammation|