Cross-talk between pro-inflammatory transcription factors and glucocorticoids

Asthma is a chronic inflammatory disease of the airway that is characterize d by cellular infiltration and activation. These processes are induced by o verexpression of chemokines and cytokines, such as eotaxin, IL-1 beta and G M-CSF. These mediators are downstream targets for the transcription factors activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), which co ntrol the expression of most immunomodulatory genes and whose activity and expression are elevated in asthma. Glucocorticoids are the most effective a nti-inflammatory drugs used in the treatment of chronic inflammatory diseas es such as asthma. They act by binding to a specific glucocorticoid recepto r (GR) that on activation translocates to the nucleus and either increases (transactivates) or decreases (transrepresses) the expression of responsive genes. Transrepression is the major mechanism of glucocorticoid action in inhibiting inflammatory gene expression. Thus, the ability of the transcipt ion factors AP-1 and NF-kappaB to induce gene transcription is attenuated b y GR. Although only 5-10% of asthmatic subjects are glucocorticoid-insensit ive, these subjects account for over 50% of the health-care costs for asthm a (> $6 billion per annum). Examining these patients also gives an insight into important aspects of glucocorticoid action in controlling inflammation and into the development of potential new drugs. Biochemical and genomic s tudies have indicated abnormal induction of the c-Jun N-terminal kinase (JN K) pathway in some of these patients. The ability of most patients to respo nd to dexamethasone with induction of histone acetylation correlated with n uclear translocation of GR. However, a subgroup of these patients had an in ability to correctly interact with the basal transcription complex in spite of high levels of nuclear GR. This suggests that cross-talk between pro- a nd anti-inflammatory transcription factors may modulate activation of the t ranscriptional complex and thereby reduce steroid actions.