SELECTED ARTICLES FROM THE RECENT LITERATURE 2006

10/16/06

How corticosteroids control inflammation

Summary
Background – The molecular mechanisms underlying corticosteroids (CS) anti- inflammatory effects are still not completely understood, despite intensive investigation.

Findings – Barnes of the National Heart and Lung Institute in London, UK reviewed findings which he feels point to the major mechanism underlying CS anti-Inflammatory effects. In inflammatory responses, pro-inflammatory genes are activated when certain pro-inflammatory transcription factors (e.g. – NF- Kappa B) bind to and activate co-activator molecules. The latter, in turn, acetylate core histories which then transcribe increased expression of the inflammatory genes. CS counteracts these actions by reversing the histone acetylation in this way. 1) CS bind to their receptors (GR) which then bind to the co-activators noted above.; 2) As a result of such GR-co-activator binding there is recruitment of histone deacetylase-2 (HDAC2), an enzyme which reverses the histone acetylation. When the GR are exposed to higher concentrations of CS, the GR interact with DNA recognition sites to stimulate transcription of anti-inflammatory genes.

Of clinical importance, impaired HDAC2 activity has been found in asthmatics who are clinically less responsive to CS therapy.

Reference
Brit J Pharmacol 2006;148:245-54

Editor's Comments
These comments by a leading asthma investigator can certainly explain a mechanism by which some individuals are relatively resistant to the beneficial effects of CS therapy. Not explained by these comments are the reasons why eosinophil-predominant allergic inflammation is inhibited much more by CS treatment than is neutrophil-predominant inflammation. Other mechanisms may also be involved in CS effects.

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