ReviewEffects of glucocorticoids on gene transcription
Section snippets
The molecular basis of inflammation in bronchial asthma
Inflammation is a central feature of bronchial asthma and involves the recruitment and activation of inflammatory cells and changes in the structural cells of the lung. These structural changes include basement membrane thickening, epithelial cell loss, airway smooth muscle hypertrophy, hyperplasia and migration in asthma and matrix destruction in emphysema. Asthma is characterized by increased expression of many proteins involved in the complex inflammatory cascade, including cytokines,
Chromatin remodeling
DNA is tightly compacted around a protein core. This chromatin structure is composed of nucleosomes, which are particles consisting of ∼146-bp DNA associated with an octamer of two molecules each of core histone proteins (H2A, H2B, H3, and H4). Expression and repression of genes is associated with alterations in chromatin structure by enzymatic modification of core histones (Urnov and Wolffe, 2001). In the resting cell, DNA is tightly compacted around these basic core histones, excluding the
Nuclear factor-κB
Although numerous different pathways are activated during the inflammatory response, NF-κB is thought to be of paramount importance in asthmatic inflammation because it is activated by all the stimuli considered important in the inflammatory response to allergen exposure (Baldwin, 2001). In addition, it is a major target for glucocorticoids (Barnes and Karin, 1997). NF-κB is ubiquitously expressed within cells, and it not only controls induction of inflammatory genes in its own right but also
Glucocorticoid-induced gene transcription
Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor that has several functional domains, including a ligand binding domain, a DNA binding domain, and two domains that are involved in transactivation of genes once binding to DNA has occurred via association with other proteins (activation function-1 and -2) (Karin, 1998). An inactive glucocorticoid receptor is bound to a protein complex that includes two subunits of the heat shock protein hsp90, which thus act
Therapeutic implications
Inhaled glucocorticoids are now used as first-line therapy for the treatment of persistent asthma in adults and children in many countries, as they are the most effective treatments for asthma currently available (Barnes and Adcock, 1998). However, at high doses systemic absorption of inhaled glucocorticoids may have deleterious effects, so there has been a search for safer steroids for inhalation and even for oral administration.
Conclusion
Advances in delineating the fundamental mechanisms of gene transcription, especially recruitment of histone-modifying cofactors, have resulted in better understanding of the molecular mechanisms whereby glucocorticoids suppress inflammation. The challenge is to see if these mechanisms hold true in primary cells in vivo. This will undoubtedly lead to the development of drugs that target novel aspects of GR function and potentially restore glucocorticoid sensitivity to diseases that are
Acknowledgments
The literature in this area is extensive, and many important studies were omitted because of constraints on space, for which we apologize. We would like to thank Drs. Borja Cosio and Gaetano Caramori for their helpful discussions.
Work in our laboratory was funded by the National Institutes of Health (USA), the British Lung Foundation, the Clinical Research Committee (Royal Brompton Hospital) and the National Asthma Campaign.
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