[Mechanism of action of glucocorticoids in asthma].
While on the basis of clinical studies glucocorticoids (GC) became the first-line therapy for asthma, the molecular basis of GC action has been extensively studied. Glucocorticoids exert their effects by binding to the glucocorticoid receptor (GR), which then inhibits or increases gene transcription through processes known as transrepression and transactivation, respectively. Transrepression results from the inhibitory interaction between the GR and other transcription factors like AP-1 and NF-kappa B. Since AP-1 and NF-kappa B DNA binding sites have been mapped to the promoter regions of many genes coding for proinflammatory mediators (IL-1, 2, 5, 6, 8, 13, TNF-alpha, RANTES, Eotaxin, GM-CSF, metalloproteinases, ICAM-1 ...), this interaction may be an important aspect of the GC anti-inflammatory properties. Transactivation is mediated through binding of the GC-activated GR to a DNA sequence called glucocorticoid response element (GRE) and may result in some benefits and side effects since GRE has been mapped to the promoter regions of genes coding for lipocortin, beta 2-adrenergic receptor, and for genes involved in the onset of metabolic effects (diabetes, hypokaliemia, hydrosodic retention) and glaucoma. Other molecular mechanisms may also be involved like the binding to the GR to a negative GRE (nGRE), the interaction with the basal transcriptional machinery, and the post transcriptional modulation of mRNA stability. In asthma, the relative importance of each mechanism remains to be studied, but both mechanisms may probably be involved.
Jaffuel
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Service des Maladies Respiratoires, INSERM U454, Hôpital Arnaud-de-Villeneuve, CHU de Montpellier.
Mathieu
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M
Godard
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P
Michel
F B
FB
Demoly
P
P
D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D005938:Glucocorticoids / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000494:pharmacology; D014158:Transcription, Genetic
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors