All patients with asthma have a specific pattern of inflammation in the airways that is characterized by degranulated mast cells, an infiltration of eosinophils, and an increased number of activated T-helper 2 cells (see Glossary) (1). It is believed that this specific pattern of inflammation underlies the clinical features of asthma, including intermittent wheezing, dyspnea, cough, and chest tightness. Suppression of this inflammation by corticosteroids controls and prevents these symptoms in most patients. Multiple mediators are produced in asthma, and the approximately 100 known inflammatory mediators that are increased in patients with asthma include lipid mediators, inflammatory peptides, chemokines, cytokines, and growth factors (2). Increasing evidence suggests that structural cells of the airways, such as epithelial cells, airway smooth-muscle cells, endothelial cells, and fibroblasts, are a major source of inflammatory mediators in asthma. Epithelial cells may play a particularly important role because they may be activated by environmental signals and may release multiple inflammatory proteins, including cytokines, chemokines, lipid mediators, and growth factors.
Figure 1. DNA is wound around an 8-histone molecule with two copies of two histones 2A, 2B, 3, and 4. Each histone molecule has a long tail rich in lysine residues ( ) that are the sites of enzymatic modification, such as acetylation, thus changing the charge of the molecule and leading to DNA unwinding.
Structure of chromatin.KGrahic Jump Location
Figure 2. Histone acetylation is mediated by coactivators, which have intrinsic histone acetyltransferase activity, whereas repression is induced by histone deacetylases ( s), which reverse this acetylation. CBP = CREB (cyclic adenosine monophosphate response element-binding protein)-binding protein; mRNA = messenger RNA; PCAF = p300/CBP-associated factor.
Gene activation and repression are regulated by acetylation of core histones.HDACGrahic Jump Location
Cellular effect of corticosteroids.Grahic Jump Location
Figure 4. Corticosteroids bind to cytoplasmic glucocorticoid receptors ( s), which translocate to the nucleus where they bind to glucocorticoid response elements ( s) in the promoter region of steroid-sensitive genes. Corticosteroids also directly or indirectly bind to coactivator molecules, such as CREB (cyclic adenosine monophosphate response element-binding protein)-binding protein ( ), p300/CBP-associated factor ( ), or steroid receptor coactivator-1 ( ), which have intrinsic histone acetyltransferase ( ) activity. This binding causes acetylation of lysines on histone-4, which leads to activation of genes encoding anti-inflammatory proteins, such as secretory leukoprotease inhibitor ( ). mRNA = messenger RNA.
How corticosteroids switch on anti-inflammatory gene expression.GRGRECBPPCAFSRC-1HATSLPIGrahic Jump Location
Figure 5. Inflammatory genes are activated by inflammatory stimuli, such as interleukin-1β ( β) or tumor necrosis factor-α ( α), resulting in activation of NF-κB kinase 2 ( ), which activates the transcription factor nuclear factor κB ( κ ). A dimer of p50 and p65 NF-κB proteins translocates to the nucleus and binds to specific κB recognition sites and also to coactivators, such as CREB (cyclic adenosine monophosphate response element-binding protein)-binding protein ( ) or p300/CBP-activating factor ( ), which have intrinsic histone acetyltransferase ( ) activity. This results in acetylation of lysines in core histone-4, resulting in increased expression of genes encoding inflammatory proteins, such as granulocyte-macrophage colony-stimulating factor ( ). Glucocorticoid receptors ( s), after activation by corticosteroids, translocate to the nucleus and bind to coactivators to inhibit HAT activity directly. They also recruit histone deacetylases ( ), which reverses histone acetylation leading in suppression of inflammatory genes. COX-2 = cyclooxygenase-2; MAPK = mitogen-activated protein kinase.
Processes by which corticosteroids switch off inflammatory genes.IL-1TNF-IKK2NF-BCBPPCAFHATGM-CSFGRHDACsGrahic Jump Location
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