Molecular mechanisms and cellular effects of glucocorticosteroids.

GCSs exert their anti-inflammatory effects through influencing multiple signal transduction pathways. Their most important action is switching off multiple activated inflammatory genes through inhibition of HAT and recruitment of HDAC2 activity to the inflammatory gene transcriptional complex. In addition, GCSs may activate several anti-inflammatory genes and increase the degradation of mRNA encoding certain inflammatory proteins. This broad array of actions may account for the striking effectiveness of GCSs in complex inflammatory diseases such as asthma and the difficulty in finding alternative anti-inflammatory drugs. There is now a better understanding of how the responsiveness to GCSs is reduced in patients who have severe asthma, who have asthma and smoke, and who have COPD. An important mechanism now emerging is a reduction in HDAC2 activity as a result of oxidative stress. These new insights into GCS action may lead to new approaches to treating inflammatory lung diseases and in particular to increasing effectiveness of steroids in situations where they are less effective.