The Journal of Steroid Biochemistry and Molecular Biology
Mechanisms and resistance in glucocorticoid control of inflammation☆
Introduction
Glucocorticoids are the most effective anti-inflammatory drugs available for the treatment many chronic inflammatory and immune diseases, including asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases. However, a minority of patients with these diseases show little or no response even to high doses of glucocorticoids. Several other inflammatory diseases, including chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis and cystic fibrosis, appear to be largely steroid-resistant. There is now a much better understanding of how glucocorticoids suppress chronic inflammation and this has given insights into the mechanisms and potential therapy of glucocorticoid resistance [1]. Glucocorticoid-resistance or insensitivity is an important barrier to effective therapy and accounts for considerable and increasing health care spending. This review describes the molecular mechanisms whereby corticosteroids so effectively suppress inflammation and then discusses the molecular basis for glucocorticoid resistance and the implications for therapy.
Section snippets
How glucocorticoids suppress inflammation
There have been major advances in understanding the molecular mechanisms whereby glucocorticoids suppress inflammation [2], [3]. Glucocorticoids activate and suppress many pro- and anti-inflammatory genes, as well as having post-transcriptional effects. Understanding the molecular mechanism of glucocorticoid action also provides new insights into molecular mechanisms of glucocorticoid resistance [1].
Molecular mechanisms of glucocorticoid resistance
Several distinct molecular mechanisms contributing to decreased anti-inflammatory effects of glucocorticoids have now been identified, so that there is heterogeneity of mechanisms even within a single disease (Table 1 and Fig. 6) [1]. However, similar molecular mechanisms have also been identified in different inflammatory diseases indicating that there may be common therapeutic approaches to glucocorticoid-resistant diseases in the future.
Therapeutic implications
Although glucocorticoids are highly effective in treating many inflammatory and immune diseases the major problem is side effects. Although this may be overcome by topical application, such as inhaled or dermal administration this is not suitable for all diseases. There has been a concerted effort to develop glucocorticoids that have reduced side effects, while retaining anti-inflammatory efficacy.
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Article from the special issue on Steroids: modulators of inflammation and immunity.