Factors Determining Glucocorticoid Sensitivity in Man

The immunosuppressive effects of glucocorticoids (GCs) are often used in the treatment of chronic inflammatory or autoimmune diseases. However, within the normal population there exists a large interindividual variation in GC sensitivity. We introduced the GILZ and IL-2 expression assays to measure small differences in GC sensitivity ex vivo by measuring the effects of GCs on transactivation of the GC-induced leucine zipper (GILZ) gene and transrepression of the interleukin-2 (IL-2) gene. Using these and other methods we characterized a group of 9 patients with affected GC sensitivity. We found differences between these patients and healthy controls in the number of GC receptors (GR) per cell, the affinity of these receptors for GCs, the presence of GR splice variants, and the effects on transactivation of GILZ and transrepression of IL-2. In this thesis, we also investigated polymorphisms in genes coding for proteins involved in the metabolism and availability of GCs, which might play a role in GC sensitivity. We showed that the HSD11B1 83,557insA en H6PD R453Q polymorphisms had no effect on body composition, andrenal androgens, blood pressure, glucose levels, and incidence of dementia in the elderly. The MDR-1 C3435T polymorphism was associated with elevated hypothalamus-pituitary-adrenal-axis activity, illustrated by higher early morning serum total cortisol and androstenedione levels (without an effect on the response to dexamethasone), but without a parallel increase in free cortisol and salivary cortisol levels. Finally, the CYP3A7*1C polymorphism was associated with significant lower dehydroepiandrosterone sulfate en estrone levels.

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