Molecular mechanisms underlying the anti-asthma action of corticosteroids

Since it is now recognized that asthma is an inflammatory disease of the airways, the powerful antiasthmatic effects of corticosteroids are believed to be largely dependent on their broad anti-inflammatory activity. These drugs are the most effective asthma treatment currently available but, although they have been used for a long time, only recently the molecular mechanisms underlying their pharmacological actions are becoming clear. Corticosteroids bind to intracellular receptors which, upon ligand-dependent activation, interact with specific genomic DNA sequences thus leading to an increase or a decrease in the transcription rate of several target genes. Modulation of gene transcription by glucocorticoids underlies complex interactions involving their receptors, genomic DNA, nuclear chromatin, and other transcription factors. Furthermore, steroid hormones can also modulate gene expression at the post-transcriptional level. The anti-inflammatory and antiasthmatic effects of corticosteroids are mediated by down- or up-regulation of specific target genes. Down-regulation of gene expression leads to a reduced synthesis of several cytokines and adhesion molecules. Up-regulation results in increased production of lipocortins and beta2-adrenergic receptors. A small minority of asthmatic patients do not respond to corticosteroids, and the mechanism underlying this steroid resistance is still under investigation.