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PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE
Physiology in Medicine
Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD, Associate Editor;William Koopman, MD, Associate Editor Annals of Internal MedicinePaul Epstein, MD, Series Editor How Do Corticosteroids Work in Asthma?
Peter J. Barnes, DM, DSc, and Ian M. Adcock, PhD
Asthma is the most common chronic disease in westernized Inflammation in asthma is characterized by the increased expression of multiple inflammatory genes, including thoseencoding for cytokines, chemokines, adhesion molecules, Patients with asthma have an underlying chronic and inflammatory enzymes and receptors.
inflammation of the airways characterized by activatedmast cells, eosinophils, and T-helper 2 lymphocytes. This Increased expression of inflammatory genes is regulated by results in increased responsiveness of the airways to such proinflammatory transcription factors, such as nuclear triggers as exercise, allergens, and air pollutants.
factor-B and activator protein-1. These bind to andactivate coactivator molecules, which then acetylate core This chronic inflammation underlies the typical symptoms of histones and switch on gene transcription.
asthma, which include intermittent wheezing, coughing,shortness of breath, and chest tightness.
Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways by reversing histone Corticosteroids are the most effective treatment for asthma, acetylation of the activated inflammatory genes.
and inhaled corticosteroids have become first-linetreatment for children and adults with persistent This mechanism acts by binding of the activated glucocorticoid receptors to coactivators and recruitment ofhistone deacetylases to the activated transcription complex.
Corticosteroids suppress the chronic airway inflammation in patients with asthma, and the molecular mechanisms Understanding how corticosteroids work in patients with involved are now being elucidated.
asthma may help in designing novel corticosteroids withless systemic effects, as well as novel anti-inflammatoryapproaches.
These molecular mechanisms of action of corticosteroids may also help elucidate the molecular basis of chronicinflammation and why corticosteroids are ineffective inpatients with steroid-resistant asthma and with chronicobstructive pulmonary disease.
Corticosteroids(orglucocorticosteroids)arewidelyused mechanisms also helps explain how corticosteroids switch
to treat various inflammatory and immune diseases.
off multiple inflammatory pathways; in addition, it pro- The most common use of corticosteroids today is in the vides insights into why corticosteroids fail to work in pa- treatment of asthma, and inhaled corticosteroids have be- tients with steroid-resistant asthma and in patients with come established as first-line treatment in adults and chil- chronic obstructive pulmonary disease (COPD).
dren with persistent asthma, the most common chronicinflammatory disease. Recent developments in understand- THE MOLECULAR BASIS OF INFLAMMATION IN ASTHMA
ing the fundamental mechanisms of gene transcription (see All patients with asthma have a specific pattern of in- Glossary) have led to major advances in understanding the flammation in the airways that is characterized by degranu- molecular mechanisms by which corticosteroids suppress lated mast cells, an infiltration of eosinophils, and an in- inflammation. This may have important clinical implica- creased number of activated T-helper 2 cells (see Glossary) tions, as it will lead to a better understanding of the in- (1). It is believed that this specific pattern of inflammation flammatory mechanisms of many diseases and may signal underlies the clinical features of asthma, including inter- the future development of new anti-inflammatory treat- mittent wheezing, dyspnea, cough, and chest tightness.
ments. The new understanding of these new molecular Suppression of this inflammation by corticosteroids con- Ann Intern Med. 2003;139:359-370.
For author affiliations, see end of text.
2003 American College of Physicians 359
Review How Do Corticosteroids Work in Asthma? Activator protein-1 (AP-1): A transcription factor that is activated by IKK2: Inhibitor of nuclear factor-B (NF-B) kinase-2 is the key enzyme that inflammatory stimuli and that increases the expression of multiple activates the NF-B in the cytoplasm to prevent it from translocating to the inflammatory genes.
nucleus to regulate inflammatory gene expression.
CREB-binding protein (CBP): A coactivator that regulates the expression of Messenger RNA (mRNA): Produced from DNA by action of RNA polymerase II.
inflammatory and other genes. It was first discovered as a binding protein forthe transcription factor CREB (cyclic adenosine monophosphate response Mitogen-activated protein (MAP) kinases: Enzymes that regulate signal element–binding protein) but has subsequently been shown to bind several transduction pathways that are involved in inflammatory and immune gene other transcription factors, including activator protein-1 and nuclear expression and cell proliferation.
Nuclear factor-B (NF-B): A transcription factor that is activated by Chromatin: The material of chromosomes. It is a complex of DNA, histones, inflammatory stimuli; it increases the expression of multiple inflammatory and nonhistone proteins found in the nucleus of a cell.
Coactivator: Nuclear protein that activates gene transcription via intrinsic p300/CBP-associated factor (PCAF): A coactivator that interacts with other histone acetyltransferase activity.
coactivators, such as CBP; similar to other coactivators, it also has histoneacetyltransferase activity.
Co-repressor: Nuclear protein that suppresses gene transcription and has histone deacetylase activity.
RNA polymerase II: The key enzyme that catalyzes the formation of messenger RNA from DNA and therefore transcription.
Glucocorticoid receptor ␣: The normal form of the glucocorticoid receptor that binds corticosteroids and translocates to the nucleus to bind to DNA.
TATA box: DNA sequence that marks the start site of gene transcription from the coding region of the gene.
Glucocorticoid receptor ␤: An alternatively spliced form of the glucocorticoid receptor that can bind to DNA (at glucocorticoid response element sites) but TATA box–binding protein (TBP): Proteins that interact with the TATA box and that does not bind corticosteroids; therefore, theoretically it may prevent also bind coactivator and related molecules.
activated glucocorticoid receptors from binding to DNA and othertranscription factors.
T-helper 2 cells: A subtype of T-helper (CD4⫹) lymphocyte that predominates in allergic diseases and that is characterized by secretion of the cytokines Glucocorticoid response element (GRE): A specific sequence of DNA in the interleukin-4, interleukin-5, and interleukin-13, which result in IgE formation promoter region of a gene, where glucocorticoid receptors bind and confer and eosinophilic inflammation.
steroid responsiveness on the gene.
Transcription: Gene expression resulting in formation of messenger RNA.
Histone: The basic protein that forms the core of the chromosome around which DNA is wound. Modification of histones by acetylation or methylation Transcription factor: Protein that binds to specific sequences in the regulatory changes their charge, and this affects DNA winding.
region of genes to switch on transcription.
Histone acetyltransferases (HATs): Enzymes that acetylate lysine residues on Transfection: Transfer of DNA sequences that may contain transcription core histones. Coactivator molecules have intrinsic histone acetyltransferase factor–binding sequences to a cell that is used to study the regulation of transcription by these transcription factors.
Histone deacetylases (HDACs): Enzymes that deacetylate acetylated core histones. About 12 such enzymes are now identified. Co-repressors haveintrinsic histone deacetylase activity.
trols and prevents these symptoms in most patients. Mul- that are activated in asthmatic airways (see Glossary) (3).
tiple mediators are produced in asthma, and the approxi- For example, NF-B is markedly activated in epithelial mately 100 known inflammatory mediators that are cells of asthmatic patients (4), and this transcription factor increased in patients with asthma include lipid mediators, regulates many of the inflammatory genes that are abnor- inflammatory peptides, chemokines, cytokines, and growth mally expressed in asthma (5). Nuclear factor-B may be factors (2). Increasing evidence suggests that structural cells activated by rhinovirus infection and allergen exposure, of the airways, such as epithelial cells, airway smooth-mus- both of which exacerbate asthmatic inflammation (6).
cle cells, endothelial cells, and fibroblasts, are a majorsource of inflammatory mediators in asthma. Epithelialcells may play a particularly important role because they may be activated by environmental signals and may release The molecular mechanisms by which inflammatory multiple inflammatory proteins, including cytokines, che- genes are switched on by transcription factors are now mokines, lipid mediators, and growth factors.
much better understood. Alteration in the structure of Inflammation is mediated by the increased expression chromatin (see Glossary) is critical to the regulation of of multiple inflammatory proteins, including cytokines, gene expression. Chromatin is made up of nucleosomes, chemokines, adhesion molecules, and inflammatory en- which are particles consisting of DNA associated with an zymes and receptors. Most of these inflammatory proteins octomer of two molecules each of the core histone proteins are regulated by increased gene transcription, which is con- (see Glossary) (H2A, H2B, H3, and H4) (Figure 1). Ex-
trolled by proinflammatory transcription factors, such as pression and repression of genes are associated with remod- nuclear factor-B (NF-B) and activator protein-1 (AP-1), eling of this chromatic structure by enzymatic modification 360 2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1)
How Do Corticosteroids Work in Asthma? Review Figure 1. Structure of chromatin.
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 lysineresidues (K) that are the sites of enzymatic modification, such as acetylation, thus changing the charge of the molecule and leading to DNA unwinding.
of core histones. Each core histone has a long terminal that scription occurs only when the chromatin structure is is rich in lysine residues that may be acetylated, thus opened up, with unwinding of DNA so that RNA poly- changing the electrical charge of the core histone. In the merase II and basal transcription complexes can now bind resting cell, DNA is wound tightly around these basic core to DNA to initiate transcription. When proinflammatory histones, excluding the binding of the enzyme RNA poly- transcription factors, such as NF-B, are activated, they merase II (see Glossary), which activates the formation of bind to specific recognition sequences in DNA and subse- messenger RNA (mRNA) (see Glossary). This conforma- quently interact with large coactivator molecules, such as tion of the chromatin structure is described as closed and is p300/CREB (cyclic adenosine monophosphate response associated with suppression of gene expression. Gene tran- element– binding protein)– binding protein (CBP) and Figure 2. Gene activation and repression are regulated by acetylation of core histones.
Histone acetylation is mediated by coactivators, which have intrinsic histone acetyltransferase activity, whereas repression is induced by histone deacety-lases (HDACs), which reverse this acetylation. CBP ⫽ CREB (cyclic adenosine monophosphate response element– binding protein)-binding protein; mRNA ⫽ messenger RNA; PCAF ⫽ p300/CBP-associated factor.
2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1) 361
Review How Do Corticosteroids Work in Asthma? p300/CBP-associated factor (PCAF) (see Glossary). These and mast cells. Epithelial cells may be a major cellular coactivator molecules act as the molecular switches that target for inhaled corticosteroids, which are the mainstay of control gene transcription. All have intrinsic histone acetyl- modern asthma management (14). Thus, corticosteroids transferase (HAT) (see Glossary) activity (7, 8), which re- have a broad spectrum of anti-inflammatory effects in sults in acetylation of core histones, thereby reducing their asthma, with inhibition of multiple inflammatory media- charge. Acetylation allows the chromatin structure to trans- tors and inflammatory and structural cells. Endogenous form from the resting closed conformation to an activated corticosteroids secreted by the adrenal cortex may also exert open form (8). This results in unwinding of DNA, binding some anti-inflammatory action, and inhibition of endoge- of TATA box– binding protein (TBP) (see Glossary), TBP- nous cortisol enhances allergic inflammation in the skin associated factors, and RNA polymerase II, which initiates (15). The broad anti-inflammatory profile of corticoste- gene transcription. This molecular mechanism is common roids probably accounts for their marked clinical effective- to all genes, including those involved in differentiation, ness in asthma. Attempts to find alternative treatments that proliferation, and activation of cells. An important step are more specific, such as inhibitors of single mediators, forward has been the discovery of the enzymes that regulate have usually been unsuccessful, emphasizing the impor- histone acetylation. Core histones are characterized by long tance of simultaneously inhibiting many inflammatory tar- N-terminal tails rich in lysine residues that are the target gets (16). Any explanation of the anti-inflammatory effects for acetylation. In general, HATs act as coactivators that of corticosteroids needs to account for this broad spectrum switch genes on; histone deacetylases (HDACs), which act of anti-inflammatory effects.
as co-repressors (see Glossary), switch genes off (Figure 2).
Recently, these fundamental mechanisms have been applied to understanding the regulation of inflammatory genes that become activated in inflammatory diseases. In Corticosteroids diffuse across the cell membrane and humans, epithelial cell line activation of NF-B (by expos- bind to glucocorticoid receptors in the cytoplasm. Cyto- ing the cell to inflammatory signals, such as interleukin- plasmic glucocorticoid receptors are normally bound to 1␤, tumor necrosis factor-␣, or endotoxin) results in acet- proteins, known as molecular chaperones, that protect the ylation of specific lysine residues on histone-4 (the other receptor and prevent its nuclear localization by covering histones do not seem to be so markedly acetylated), and the sites on the receptor that are needed for transport this is correlated with increased expression of inflammatory across the nuclear membrane into the nucleus. A single genes, such as granulocyte-macrophage colony-stimulating gene encodes glucocorticoid receptors, but several variants factor (GM-CSF) (9). The acetylation of histone that is are now recognized (17). Glucocorticoid receptor ␣ binds associated with increased expression of inflammatory genes corticosteroids, whereas glucocorticoid receptor ␤ is an al- is counteracted by the activity of HDACs (more than 12 ternatively spliced form that binds to DNA but is not that are associated with gene suppression have been char- activated by corticosteroids (see Glossary). Glucocorticoid acterized ). In biopsy samples from patients with receptor ␤ has been implicated in steroid resistance in asthma, HAT activity is increased and HDAC activity is asthma (18), although whether glucocorticoid receptor ␤ decreased, thus favoring increased inflammatory gene ex- has any functional significance has been questioned (19).
pression (11). Improved understanding of the molecular Glucocorticoid receptors may also be modified by phos- basis of asthma has helped to explain how corticosteroids phorylation and other modifications, which may alter the are so effective in suppressing this complex inflammation response to corticosteroids. For example, several serines or that involves many cells, mediators, and inflammatory ef- threonines are in the N-terminal domain, where glucocor- ticoid receptors may be phosphorylated by various kinases;this may change corticosteroid-binding affinity, nuclearimport and export, receptor stability, and transactivating CELLULAR EFFECTS OF CORTICOSTEROIDS
Corticosteroids are the only therapy that suppresses After corticosteroids have bound to glucocorticoid re- the inflammation in asthmatic airways; this action under- ceptors, changes in the receptor structure result in dissoci- lies the clinical improvement in asthma symptoms and pre- ation of molecular chaperone proteins, thereby exposing vention of exacerbations (12, 13). At a cellular level, corti- nuclear localization signals on glucocorticoid receptors.
costeroids reduce the number of inflammatory cells in the This results in rapid transport of the activated glucocorti- airways, including eosinophils, T lymphocytes, mast cells, coid receptor– corticosteroid complex into the nucleus, and dendritic cells (Figure 3). These remarkable effects of
where it binds to DNA at specific sequences in the pro- corticosteroids are produced through inhibiting the recruit- moter region of steroid-responsive genes known as glu- ment of inflammatory cells into the airway by suppressing cocorticoid response elements (GRE) (see Glossary). Two the production of chemotactic mediators and adhesion glucocorticoid receptor molecules bind together as a homo- molecules and by inhibiting the survival in the airways of dimer and bind to GRE, leading to changes in gene tran- inflammatory cells, such as eosinophils, T lymphocytes, 362 2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1)
How Do Corticosteroids Work in Asthma? Review therapeutic doses of inhaled corticosteroids have not been Corticosteroids produce their effect on responsive cells shown to increase annexin-1 concentrations in bronchoal- by activating glucocorticoid receptors to directly or indi- veolar lavage fluid (25), and an increase in IB-␣ has not rectly regulate the transcription of target genes (21). The been shown in most cell types, including epithelial cells number of genes per cell directly regulated by corticoste- (26, 27). It seems highly unlikely that the widespread anti- roids is estimated to be between 10 and 100, but many inflammatory actions of corticosteroids could be explained genes are indirectly regulated through an interaction with by increased transcription of small numbers of anti-inflam- other transcription factors and coactivators. Glucocorticoid matory genes, particularly because high concentrations of receptor dimers bind to DNA at GRE sites in the promoter corticosteroids are usually required for this response, whereas region of steroid-responsive genes. Interaction of the acti- in clinical practice, corticosteroids can suppress inflamma- vated glucocorticoid receptor dimer with GRE usually in- tion at much lower concentrations.
creases transcription, resulting in increased protein synthe- Little is known about the molecular mechanisms of sis. Glucocorticoid receptor may increase transcription by corticosteroid side effects, such as osteoporosis, growth re- interacting with coactivator molecules, such as CBP and tardation in children, skin fragility, and metabolic effects.
PCAF, thus switching on histone acetylation and gene These actions of corticosteroids are related to their endo- transcription. For example, relatively high concentrations crine effects. The systemic side effects of corticosteroids of corticosteroids increase the secretion of the antiprotease may be due to gene activation. Some insight into this has secretory leukoprotease inhibitor from epithelial cells (9).
been provided by mutant glucocorticoid receptors, which The activation of genes by corticosteroids is associated do not dimerize and therefore cannot bind to GRE to with a selective acetylation of lysine residues 5 and 16 on switch on genes. Transgenic mice that express these mutant histone-4, resulting in increased gene transcription (9, 22) glucocorticoid receptor corticosteroids show no loss of (Figure 4). Activated glucocorticoid receptors may bind to
anti-inflammatory effect and can suppress NF-B–acti- coactivator molecules, such as CBP or PCAF, as well as vated genes in the normal way (28).
steroid-receptor coactivator-1, which itself has HAT activ-ity (23, 24). However, steroid-receptor activator-1 does notseem to be involved in NF-B–activated HAT activity (9), SWITCHING OFF INFLAMMATORY GENES
but other similar coactivator molecules are probably in- In controlling inflammation, the major effect of corti- volved. Corticosteroids may suppress inflammation by in- costeroids is to inhibit the synthesis of many inflammatory creasing the synthesis of anti-inflammatory proteins, such proteins through suppression of the genes that encode as annexin-1, secretory leukoprotease inhibitor, interleu- them. This effect was originally believed to occur through kin-10, and the inhibitor of NF-B, IB-␣. However, interaction of glucocorticoid receptors with GRE sites that Figure 3. Cellular effect of corticosteroids.
2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1) 363
Review How Do Corticosteroids Work in Asthma? Figure 4. How corticosteroids switch on anti-inflammatory gene expression.
Corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs), which translocate to the nucleus where they bind to glucocorticoid response elements(GREs) in the promoter region of steroid-sensitive genes. Corticosteroids also directly or indirectly bind to coactivator molecules, such as CREB (cyclicadenosine monophosphate response element– binding protein)-binding protein (CBP), p300/CBP-associated factor (PCAF), or steroid receptor coacti-vator-1 (SRC-1), which have intrinsic histone acetyltransferase (HAT) activity. This binding causes acetylation of lysines on histone-4, which leads toactivation of genes encoding anti-inflammatory proteins, such as secretory leukoprotease inhibitor (SLPI). mRNA ⫽ messenger RNA.
switched off transcription and are termed negative GREs (in activated glucocorticoid receptors can interact directly with contrast to the usual type of GRE that is associated with activated transcription factors by protein–protein interac- increased transcription). However, these negative GREs tion, but this may be a feature of cells in which these genes have only rarely been demonstrated and are not a feature of are artificially overexpressed rather than a property of nor- the promoter region of the inflammatory genes that are mal cells. Treatment of asthmatic patients with high doses suppressed by steroids in the treatment of asthma. Patients of inhaled corticosteroids that suppress airway inflamma- with asthma have increased expression of many inflamma- tion does not reduce NF-B binding to DNA (29). This tory genes, including those encoding cytokines, chemo- suggests that corticosteroids are more likely to be acting kines, adhesion molecules, inflammatory enzymes, and in- downstream of the binding of proinflammatory transcrip- flammatory receptors (Table).
tion factors to DNA, and attention has now focused on Interaction with Transcription Factors
their effects on chromatin structure and histone acetyla- Activated glucocorticoid receptors interact function- ally with other activated transcription factors. Most of the Effects on Histone Acetylation
inflammatory genes that are activated in asthma do not Repression of genes occurs through reversal of the hi- have GREs in their promoter regions yet are potently re- stone acetylation that switches on inflammatory genes (30).
pressed by corticosteroids. The evidence is persuasive that Activated glucocorticoid receptors may bind to CBP or corticosteroids inhibit the effects of proinflammatory tran- other coactivators directly to inhibit their HAT activity scription factors, such as AP-1 and NF-B, that regulate (9), thus reversing the unwinding of DNA around core the expression of genes that code for many inflammatory histones and thereby repressing inflammatory genes. More proteins, such as cytokines, inflammatory enzymes, adhe- important, particularly at low concentrations that are likely sion molecules, and inflammatory receptors (3, 5). The to be relevant therapeutically in asthma treatment, acti- 364 2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1)
How Do Corticosteroids Work in Asthma? Review vated glucocorticoid receptors recruit HDACs to the acti- Table. Effect of Corticosteroids on Gene Transcription*
vated transcriptional complex, resulting in deacetylation ofhistones and thus a decrease in inflammatory gene tran- Annexin-1 (lipocortin-1, phospholipase A2 inhibitor) scription (9) (Figure 5). At least 12 HDACs have now
␤2-adrenergic receptor been identified, and these are differentially expressed and Secretory leukocyte inhibitory protein regulated in different cell types (10). Evidence now shows Clara cell protein (CC10, phospholipase A2 inhibitor)IL-1 receptor antagonist that the different HDACs target different patterns of acet- IL-1R2 (decoy receptor) ylation (31). These differences in HDACs may contribute IB␣ (inhibitor of NF-B) to differences in responsiveness to corticosteroids among IL-10 (indirectly) different genes and cells.
An important question is why corticosteroids switch IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-12, IL-13, IL-16, IL-17, off only inflammatory genes; they clearly do not suppress IL-18, TNF-␣, GM-CSF, SCF all activated genes and are well tolerated as a therapy. Glu- IL-8, RANTES, MIP-1␣, MCP-1, MCP-3, MCP-4, eotaxin cocorticoid receptors probably bind only to coactivators Adhesion molecules that are activated by proinflammatory transcription factors, ICAM-1, VCAM-1, E-selectin Inflammatory enzymes such as NF-B and AP-1, although we do not understand Inducible nitric oxide synthase how this specific recognition occurs. It is likely that several Inducible cyclooxygenase specific coactivators interact with glucocorticoid receptors.
Cytoplasmic phospholipase A2 Inflammatory receptors Activator protein-1 and NF-B repression is normal in Tachykinin NK1-receptors, NK2-receptors mice that express a form of glucocorticoid receptors that Bradykinin B2-receptors does not dimerize (dim⫺/⫺), indicating that glucocorticoid receptor monomers can mediate the anti-inflammatory ef-fects of corticosteroids, whereas dimerization is needed for * GM-CSF ⫽ granulocyte-macrophage colony-stimulating hormone; ICAM ⫽ gene activation (21, 28).
intercellular adhesion molecule-1; IL ⫽ interleukin; MCP ⫽ monocyte chemoat- tractant protein; MIP ⫽ macrophage inflammatory protein; NF-B ⫽ nuclear fac- Other Histone Modifications
tor-B; RANTES ⫽ regulated upon activation, normal cell expressed and secreted; SCF ⫽ stem-cell factor; TNF-␣ ⫽ tumor necrosis factor-␣; VCAM-1 ⫽ vascular It has recently become apparent that core histones may cell adhesion molecule-1.
also be modified not only by acetylation but also by meth-ylation, phosphorylation, and ubiquitination and that sion through the regulation of proinflammatory transcrip- these modifications may regulate gene transcription (32).
tion factors. Increasing evidence shows that corticosteroids Methylation of histones, particularly histone-3, by histone may exert an inhibitory effect on these pathways. Cortico- methyltransferases, results in gene suppression (33). The steroids may inhibit AP-1 and NF-B via an inhibitory anti-inflammatory effects of corticosteroids are reduced by effect on c-Jun N-terminal kinases, which activate these a methyltransferase inhibitor, 5-aza-2⬘-deoxycytidine, sug- transcription factors (37, 38). Corticosteroids reduce the gesting that this may be an additional mechanism by which stability of mRNA for some inflammatory genes, such as corticosteroids suppress genes (34). Indeed, there may be cyclooxygenase-2, through an inhibitory action on another an interaction between acetylation, methylation, and phos- MAP kinase, p38 MAP kinase (39). This inhibitory effect phorylation of histones, so that the sequence of chromatin is mediated via the induction of a potent endogenous in- modifications may give specificity to expression of particu- hibitor of p38 MAP kinase called MAP kinase phospha- lar genes (35).
Although most of the actions of corticosteroids are INTERACTIONS BETWEEN CORTICOSTEROIDS AND
mediated by changes in transcription through chromatin OTHER DRUGS
remodeling, it is increasingly recognized that they may also Patients with asthma are usually treated with inhaled affect protein synthesis by reducing the stability of mRNA so that less protein is synthesized. Some inflammatory 2-agonists as bronchodilators and inhaled corticosteroids as anti-inflammatory treatment. Indeed, fixed combination genes, such as the gene encoding GM-CSF, produce inhalers of long-acting ␤ mRNA that is particularly susceptible to the action of ri- 2-agonists and corticosteroids are now available and seem to be the most effective way to bonucleases that break down mRNA, thus switching off control asthma because these two classes of drug have com- protein synthesis. Corticosteroids may have inhibitory ef- plementary and synergistic effects (41). Corticosteroids in- fects on the proteins that stabilize mRNA, leading to more crease the expression of ␤ rapid breakdown and thus a reduction in protein expres- 2-adrenergic receptors in the lung and prevent their downregulation and uncoupling in re- sponse to ␤2-agonists (42– 44). Recent studies also show Effects on Mitogen-Activated Protein Kinases
that ␤2-agonists enhance the action of corticosteroids, with Mitogen-activated protein (MAP) (see Glossary) ki- an increase in nuclear translocation of glucocorticoid re- nases play an important role in inflammatory gene expres- ceptors in vitro (45) and enhanced suppression of inflam- 2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1) 365
Review How Do Corticosteroids Work in Asthma? Figure 5. Processes by which corticosteroids switch off inflammatory genes.
Inflammatory genes are activated by inflammatory stimuli, such as interleukin-1␤ (IL-1␤) or tumor necrosis factor-␣ (TNF-␣), resulting in activation of NF-B kinase 2 (IKK2), which activates the transcription factor nuclear factor B (NF-B). A dimer of p50 and p65 NF-B proteins translocates to the nucleus and binds to specific B recognition sites and also to coactivators, such as CREB (cyclic adenosine monophosphate response element– binding protein)-binding protein (CBP) or p300/CBP-activating factor (PCAF), which have intrinsic histone acetyltransferase (HAT) activity. This results inacetylation of lysines in core histone-4, resulting in increased expression of genes encoding inflammatory proteins, such as granulocyte-macrophagecolony-stimulating factor (GM-CSF). Glucocorticoid receptors (GRs), after activation by corticosteroids, translocate to the nucleus and bind to coacti-vators to inhibit HAT activity directly. They also recruit histone deacetylases (HDACs), which reverses histone acetylation leading in suppression ofinflammatory genes. COX-2 ⫽ cyclooxygenase-2; MAPK ⫽ mitogen-activated protein kinase.
matory genes (46, 47). Nuclear localization of glucocorti- mens from asthmatic patients, and the increase in HDAC coid receptors is also enhanced after treatment of asthmatic activity is correlated with the reduction in airway eosino- patients with a combination inhaler compared with the phils (50). Because corticosteroids also activate HDAC, same dose of inhaled steroid given alone (48). The molec- but via a different mechanism, theophylline should en- ular mechanisms that result in increased nuclear localiza- hance the anti-inflammatory actions of corticosteroids; this tion of glucocorticoid receptors are not yet known but may enhancement occurs because the HDAC recruited to the involve phosphorylation of glucocorticoid receptors or an inflammatory gene will be more effective at switching off effect on nuclear transport proteins.
the gene. Indeed, therapeutic concentrations of theophyl- Theophylline has been used to treat asthma for many line markedly potentiate the anti-inflammatory effects of years, but its mechanism of action has been difficult to corticosteroids in vitro (50). This effect may explain why elucidate. Originally, theophylline was used as a broncho- adding a low dose of theophylline is more effective than dilator; it relaxes airway smooth muscle by inhibiting phos- increasing the dose of inhaled corticosteroids in patients phodiesterases. Accumulating evidence indicates that at whose asthma is not adequately controlled (51–53).
lower doses, theophylline has anti-inflammatory effects,but these are probably not mediated by phosphodiesterase inhibition because the inhibition of these enzymes is trivial Although corticosteroids are highly effective in the at low plasma concentrations that are clinically effective control of asthma and other chronic inflammatory or im- (49). We have recently shown that the anti-inflammatory mune diseases, a small proportion of patients with asthma effects of theophylline may be mediated via activation of do not respond even to high doses of oral corticosteroids HDAC and that this effect is independent of phosphodi- (54, 55). Resistance to the therapeutic effects of corticoste- esterase inhibition (50). Low doses of theophylline signifi- roids is also recognized in other inflammatory and immune cantly increase HDAC activity in bronchial biopsy speci- diseases, including rheumatoid arthritis and inflammatory 366 2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1)
How Do Corticosteroids Work in Asthma? Review bowel disease. Corticosteroid-resistant patients, although inflammatory action of high doses of corticosteroids.
uncommon, present considerable management problems.
Whether this is a genetic defect is not yet known.
The new insights into the mechanisms by which cortico- Corticosteroid Resistance in COPD
steroids suppress chronic inflammation have shed light on Although inhaled corticosteroids are highly effective in the molecular basis for corticosteroid resistance in asthma.
asthma, they provide little benefit in COPD even though There is probably a spectrum of steroid responsiveness, airway and lung inflammation is present. In COPD, in- with steroid resistance at one end; however, relative resis- flammation is not suppressed by corticosteroids and there tance is seen in patients who require high doses of inhaled is no reduction in inflammatory cells, cytokines, or pro- and oral steroids (steroid-dependent asthma). Biopsy stud- teases in induced sputum, even with oral corticosteroids ies have demonstrated the typical eosinophilic inflamma- (63, 64). Corticosteroids do not suppress neutrophilic in- tion of asthma in these patients (54).
flammation in the airways, and corticosteroids may pro-long the survival of neutrophils (65). Some evidence shows Molecular Mechanisms of Corticosteroid Resistance
that an active steroid resistance mechanism exists in There may be several mechanisms for resistance to the COPD. For instance, in patients with COPD, corticoste- effects of corticosteroids, and these may differ among pa- roids do not inhibit cytokines that they normally suppress.
tients. Certain cytokines (particularly interleukin-2, inter- In vitro studies show that cytokine release from alveolar leukin-4, and interleukin-13, which show increased expres- macrophages is markedly resistant to the anti-inflammatory sion in bronchial biopsy samples from patients with effects of corticosteroids compared with cells from normal steroid-resistant asthma) may induce a reduction in affinity smokers; these, in turn, are more resistant than alveolar of glucocorticoid receptors in inflammatory cells, such as T macrophages from nonsmokers (66). This lack of response lymphocytes, resulting in local resistance to the anti- to corticosteroids may be explained, at least in part, by an inflammatory actions of corticosteroids (54, 56). We have inhibitory effect of cigarette smoking and oxidative stress recently demonstrated that the combination of interleu- on HDACs, thus interfering with the critical anti-inflam- kin-2 and interleukin-4 induces steroid resistance in vitro matory action of corticosteroids (67). There is a striking through activation of p38 MAP kinase, which phosphory- reduction in the activity and expression of HDACs in the lates glucocorticoid receptors and reduces corticosteroid- peripheral lung of patients with COPD (68). Even in pa- binding affinity and steroid-induced nuclear translocation tients with COPD who have stopped smoking, the steroid of glucocorticoid receptors (57). The therapeutic implica- resistance persists (63, 64), and these patients are known to tion is that p38 MAP kinase inhibitors now in clinical have continuing oxidative stress (69).
development might reverse this steroid resistance.
Another proposed mechanism for steroid resistance in asthma is increased expression of glucocorticoid receptor ␤, which may theoretically act as an inhibitor by competing Because inhaled corticosteroids are the most effective with glucocorticoid receptor ␣ for binding to GRE sites or currently available treatment for asthma, they are now used from interacting with coactivator molecules (58). How- as first-line therapy for persistent asthma in adults and chil- ever, expression of glucocorticoid receptor ␤ is not in- dren in many countries (70). However, at high doses, sys- creased in the mononuclear cells of patients with steroid- temic absorption of inhaled corticosteroids may have dele- dependent asthma (who have a reduced responsiveness to terious effects; therefore, investigators have searched for safer corticosteroids in vitro), and glucocorticoid receptor ␣ steroids for inhalation and even for oral administration.
greatly predominates over glucocorticoid receptor ␤, mak- ing it unlikely that it could have any functional inhibitory All currently available inhaled corticosteroids are effect (59).
absorbed from the lungs into the systemic circulation; there- In patients with steroid-resistant and steroid-depen- fore, inevitably they have some systemic component. Under- dent asthma, the inhibitory effect of corticosteroids on cy- standing the molecular mechanisms of action of corticoste- tokine release is reduced in peripheral blood mononuclear roids has led to the development of a new generation of cells (60, 61). In one group of patients, nuclear localization corticosteroids. The major task in developing these drugs is of glucocorticoid receptors in response to a high concen- to dissociate the anti-inflammatory effects from the endo- tration of corticosteroids was impaired, and this may be crine actions that are associated with side effects. As dis- due to such abnormalities as the increased activation of cussed earlier, a major mechanism of the anti-inflammatory p38 MAP kinase described earlier. However, in another effect of corticosteroids seems to be inhibition of the effects group of patients, nuclear localization of glucocorticoid re- of proinflammatory transcription factors, such as NF-B ceptors was normal, and there was a defect in acetylation of and AP-1, which are activated by proinflammatory cytokines histone-4 (62). In this group of patients, specific acetyla- (transrepression) via an inhibitory action on histone acetyla- tion of lysine 5 was defective; presumably, corticosteroids tion and stimulation of histone deacetylation. By contrast, cannot activate certain genes that are critical to the anti- the endocrine and metabolic effects of steroids that are 2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1) 367
Review How Do Corticosteroids Work in Asthma? responsible for the systemic side effects of corticosteroids are tional effects of NF-B, and small-molecule inhibitors of likely to be mediated predominantly via DNA binding IB kinase-2 (IKK2) (see Glossary), which activate NF-B, (transactivation). This speculation has led to a search for are in development. However, because corticosteroids have novel corticosteroids that selectively transrepress without additional effects, it is not certain whether IKK2 inhibitors significant transactivation, thus reducing the potential risk will parallel the clinical effectiveness of corticosteroids; they for systemic side effects. Because corticosteroids bind to the may have side effects, such as increased susceptibility to same glucocorticoid receptors, this seems at first to be an unlikely possibility, but while DNA binding involved a Treatments that bypass or reverse steroid resistance are glucocorticoid receptor homodimer, interaction with tran- also needed. p38 MAP kinase inhibitors might reduce ste- scription factors AP-1 and NF-B and coactivators involves roid resistance and act as anti-inflammatory treatments in only a single glucocorticoid receptor (22). A separation of patients with some forms of steroid-resistant asthma; how- transactivation and transrepression has been demonstrated ever, these inhibitors would not be expected to benefit by using reporter gene constructs in transfected (see Glos- patients with the form of steroid resistance associated with sary) cells using selective mutations of the glucocorticoid a defect in acetylation of lysine 5 on histone-4. In patients receptor (71). In addition, in mice with glucocorticoid re- with COPD, there is an urgent need to develop novel ceptors that do not dimerize, there is no transactivation, but anti-inflammatory treatments or to reverse corticosteroid transrepression seems to be normal (21, 28). Furthermore, resistance (76). Because oxidative stress seems to inhibit some steroids, such as the antagonist RU486, have a greater HDAC activity and mimic the defect in HDAC seen in transrepression than transactivation effect. Indeed, the topi- patients with COPD, antioxidants might be expected to be cal steroids used in asthma therapy today, such as fluticasone effective. Similarly, low-dose theophylline, by increasing propionate and budesonide, seem to have more potent tran- HDAC activity, may also reverse corticosteroid resistance srepression than transactivation effects, which may account in patients with COPD (77).
for their selection as potent anti-inflammatory agents (72).
Recently, a novel class of steroids with potent transrepression From National Heart and Lung Institute, Imperial College, London, and relatively little transactivation has been described. These United Kingdom.
"dissociated" steroids, including RU24858 and RU40066, Potential Financial Conflicts of Interest: Grants received: P.J. Barnes,
have anti-inflammatory effects in vitro (73), although there I.M. Adcock (GlaxoSmithKline and AstraZeneca); Grants pending: P.J.
is little separation of anti-inflammatory effects and systemic Barnes, I.M. Adcock (GlaxoSmithKline and AstraZeneca).
side effects in vivo (74). Several dissociated corticosteroidsare now in clinical development and show good separation Requests for Single Reprints: P.J. Barnes, DM, DSc, Department of
between transrepression and transactivation actions. This Thoracic Medicine, National Heart and Lung Institute, Dovehouse suggests that the development of steroids with a greater Street, London SW3 6LY, United Kingdom; e-mail, firstname.lastname@example.org.
margin of safety is possible and may even lead to the devel-opment of oral steroids that do not have significant adverse effects. The recent resolution of the crystal structure of 1. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001;344:350-62.
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al. Impaired inhibition by dexamethasone of cytokine release by alveolar macro-
histone deacetylase activity and restores glucocorticoid function during oxidative phages from patients with chronic obstructive pulmonary disease. Am J Respir stress [Abstract]. Am J Respir Crit Care Med. 2002;165:A625.
370 2 September 2003 Annals of Internal Medicine Volume 139 • Number 5 (Part 1)
University of Rhode Island The Impact of New Social Media on Intercultural Follow this and additional works at: Part of the nd the Recommended CitationSawyer, Rebecca, "The Impact of New Social Media on Intercultural Adaptation" (2011). Senior Honors Projects. Paper 242. This Article is brought to you for free and open access by the Honors Program at the University of Rhode Island at DigitalCommons@URI. It has beenaccepted for inclusion in Senior Honors Projects by an authorized administrator of DigitalCommons@URI. For more information, please contact.