[Role of glucocorticosteroid receptors in bronchial asthma].
Glucocorticoids (GC) represent the cornerstone anti-inflammatory treatment of chronic asthma. A small proportion of asthmatics develop a severe form of the disease and require a chronic long-term treatment with oral GC. These patients, ascribed as GC dependent asthmatics, present an ongoing inflammation of the airways. GC dependent asthma should be differentiated from GC resistant asthma. GC resistant asthmatics are defined as patients whose baseline pre-bronchodilation FEV1 of less than 70-80% predicted improves by less than 15% following 1-2 weeks of 40 mg prednisolone daily. The effects of GC are mediated by the GC receptor (GR) alpha. By a process called trans-activation they increase the transcription of genes involved in either beneficial processes or certain side effects. Through trans-repression, they inhibit the transcription factors, including nuclear factor kappa B (NF-kappa B), thereby decreasing the expression of many genes encoding inflammatory mediators. In addition to GR alpha, an isoform deficient in hormone binding has been isolated in humans and termed GR beta, which functions as a dominant negative inhibitor of GR alpha. However, to act as such, GR beta has to be more abundant than GR alpha, and conflicting data have been obtained concerning the relative levels of the two isoforms in cell lines and freshly isolated cells. It seems however that overexpression of GR beta may play a role in GC-resistant asthmatics, whereas in GC-dependent asthmatics, a predominant GR alpha expression has been consistently found. Thus the persistence of inflammation in GC-dependent asthma does not seem to be associated with an overexpression of GR beta but with a dysfunction of the trans-repression or trans-activation processes mediating the anti-inflammatory effects of GR alpha.
Gagliardo
R
R
Vignola
A M
AM
Bonsignore
G
G
D001249:Asthma / Q000209:etiology*; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000502:physiology*
D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta