Version July 2025
INTRODUCTION —
Inhaled glucocorticoids (ie, glucocorticosteroids, corticosteroids, steroids) suppress airway inflammation by activating anti-inflammatory genes, switching off inflammatory gene expression, and inhibiting inflammatory cells. In addition, they enhance beta 2 adrenergic signaling by increasing beta 2-receptor expression and function. The net effect is control of the symptoms and signs of asthma in most patients.
The molecular effects of inhaled glucocorticoids in asthmatic airways are discussed in this topic review. In addition, the molecular determinants of glucocorticoid sensitivity are reviewed. The pharmacology of glucocorticoids, the role of inhaled glucocorticoids in the management of asthma, and the potential adverse effects of inhaled glucocorticoids are presented separately.
●(See "Overview of the pharmacologic use of glucocorticoids".)
●(See "An overview of asthma management in children and adults".)
●(See "Glucocorticoid resistance in asthma".)
●(See "Major side effects of inhaled glucocorticoids".)
SUPPRESSION OF INFLAMMATION —
Discoveries related to gene transcription have improved our understanding of the mechanisms by which inhaled glucocorticoids suppress airway inflammation [1,2]. These mechanisms include anti-inflammatory gene activation and switching off inflammatory gene expression, which alter the expression of inflammatory and anti-inflammatory enzymes, receptors, cytokines, adhesion molecules, and chemokines. The net effect is decreased inflammatory cell recruitment, survival, and accumulation.
Anti-inflammatory gene activation — There are two types of glucocorticoid receptors (GR), GR alpha and GR beta. Glucocorticoid action is facilitated by GR alpha, but potentially inhibited by GR beta.
●GR alpha – Glucocorticoids passively diffuse across the cell membrane and bind to GR alpha in the cytoplasm [2]. The glucocorticoid/GR alpha complex (ie, activated GR) rapidly translocates into the nucleus. There, the activated GR form dimers, which bind to glucocorticoid response elements (GREs) within the promoter of glucocorticoid-responsive genes. There are positive and negative GREs.
Interaction with positive GREs stimulates gene transcription. Such genes usually encode anti-inflammatory proteins [3]. As an example, glucocorticoids stimulate the expression of secretory leukoprotease inhibitor and mitogen-activated protein kinase phosphatase-1 (MKP-1), which inhibit mitogen-activated protein (MAP) kinase pathways (figure 1) [4]. Interaction with positive GREs appears to account for most of the side effects of glucocorticoids [5]. As an example, binding the GR to the promoter site on the osteocalcin gene interferes with its transcription, resulting in reduced expression and reduction in bone synthesis.
Interaction with negative GREs suppresses gene transcription, but there are only a few examples of reduced expression of inflammatory genes through interaction with negative GREs, indicating that other molecular mechanisms are involved in the suppression of inflammation.
●GR beta – GR beta is an alternatively spliced form of GR. It binds DNA, but not glucocorticoids. As a result, GR beta may act as an inhibitor of glucocorticoid action by antagonizing the binding of GR alpha dimers to DNA, although the amounts of GR beta are thought to be too small to cause significant inhibition of glucocorticoid effects [6]. GR-beta is up-regulated in glucocorticoid-resistant asthma [7].
Switching off inflammatory genes — In all inflammatory diseases, including asthma, many inflammatory genes are activated. These include genes that encode cytokines, chemokines, adhesion molecules, inflammatory enzymes, and receptors. Such genes are switched on when a coactivator molecule (eg, CREB-binding protein) binds to a proinflammatory transcription factor (eg, nuclear factor-kappa B [NF-kB], activator protein-1 [AP-1]). The coactivator molecule then acetylates core histones, which opens the chromatin structure and allows transcription to proceed [8].
There are several ways in which inhaled glucocorticoids interfere with this process and switch off the inflammatory cascade:
●Glucocorticoids interact with the coactivator molecules and inhibit their binding to proinflammatory transcription factors [1,9]. In detail:
•There are clusters of dexamethasone-regulated genes showing temporal and size differences in up- and down-regulating genes [10]. This involves the recruitment of chromatin remodeling complexes such as SWI/SNF (SWItch/Sucrose NonFermentable) that alter the chromatin structure and evict GR from DNA after 10 to 20 seconds [11].
•Furthermore, modulation of gene induction and repression by activated GR involves tethering of activated GR to other prebound transcription factors such as the pioneer factor AP-1 at accessible chromatin foci that have preformed chromatin interactions [12] resulting in an extensive AP-1-GR interactome in GR-exposed cells [13]. Indeed, 95 percent of GR genomic binding occurs at preexisting foci of accessible chromatin [14].
•GR binding increases chromatin foci interactions with distal GR sites, with GR-induced genes having enhanced associations with transcriptionally active chromosome compartments. In contrast, the converse occurs for GR-repressed genes [15].
•Finally, this GR-DNA interaction enables the recruitment of transcriptional coactivators or repressors into selective gene activator or repressor condensates or modules via specific protein motifs to switch genes on or off respectively [16].
●Activated GR recruit histone deacetylase-2 (HDAC2), which deacetylates core histones. HDAC2 has broad impact, suppressing all activated inflammatory genes within the nucleus (figure 2).
●GR is normally acetylated and binds to DNA in its acetylated form. It has to be deacetylated by HDAC2 in order to inhibit NF-kB [17].
●GR is translocated into the nucleus via the nuclear import protein importin-alpha [18]. The transcription factor GATA3 in T-helper 2 (Th2) lymphocytes regulates the expression of Th2 cytokines (interleukin [IL]-4, IL-5, and IL-13), which orchestrate allergic inflammation. GATA3 is also imported into the nucleus via importin-alpha, but activated GR takes precedence, preventing the nuclear import of GATA3, and thus rapidly inhibiting the expression of Th2 cytokines and suppressing allergic inflammation [19].
Regardless of the mechanism, the net effect is the incorrect modulation of chromatin structure for the required activation or repression of anti-inflammatory or inflammatory genes respectively. Inhaled glucocorticoids preferentially impact inflammatory genes and do so primarily on a local level. Thus, they are effective at controlling asthma and are associated with few adverse effects.
Transcriptional signatures — Gene expression analysis of the acute (six-hour) and subacute (four-week) effects of inhaled budesonide on lower airway epithelium of healthy subjects has been reported [20,21]. Acute budesonide treatment up-regulated 46 genes, many of which were associated with transcriptional regulation, cell-cell communication, and anti-inflammatory intracellular signaling [20]. Longer-term treatment with budesonide identified upregulation of 72 genes in bronchial brushings and 53 genes in bronchial biopsies and down-regulation of 82 and 416 genes, respectively [21]. The most down-regulated genes reflected pathways associated with T2 inflammation, B- and T-cell regulated immunity, as well as innate immunity.
A confounding factor in the analysis of glucocorticoid actions in the airways is disease status. Further research is needed to determine which transcriptional mechanisms are relevant in patients with asthma. There have been past examples of glucocorticoid-mediated effects that were detected experimentally but could not subsequently be confirmed in patients. Specifically, the activated GR directly interacts with transcription factors and inhibits their activity in experimental systems but not in patients with asthma [22].
Gene signatures obtained from the above studies of healthy patients can be used to indicate degrees of glucocorticoid responsiveness in the airways of patients with different severities of asthma to understand whether glucocorticoids are acting similarly in the setting of airway disease. They may also be used to examine similarities and differences between the effects of biologics and inhaled glucocorticoids on the respiratory epithelium.
Post-transciptional mechanisms — There may also be post-transcriptional mechanisms by which glucocorticoids switch off inflammation. As an example, some inflammatory genes (eg, granulocyte-macrophage colony stimulating factor) normally have an unstable messenger RNA that is rapidly degraded by RNAses. Inflammatory mediators stabilize this messenger RNA during inflammation. Glucocorticoids reverse this effect, allowing rapid degradation of mRNA and reduced inflammatory protein secretion [23]. The mechanism of action is uncertain but may be glucocorticoid-mediated inhibition of the proteins that stabilize mRNAs, such as tristetraprolin [24], the zinc finger proteins ZFP36L1 and L2 [25] possibly following up-regulation of MKP-1 [26].
Additionally, some effects of glucocorticoids may be mediated through nongenomic effects that are GR-independent and not blocked by the GR antagonist RU486 [27]. These responses include rapid effects on calcium signaling, apoptosis of inflammatory cells, and endothelial nitric oxide synthase, but whether these are relevant to the action of glucocorticoids in airway disease is uncertain.
Inflammatory cell inhibition — By activating anti-inflammatory genes and switching off inflammatory gene expression, inhaled glucocorticoids inhibit inflammatory cell survival and suppress production of chemotactic mediators and adhesion molecules. The net effect is decreased mucosal inflammation, which is characterized by fewer inflammatory cells, including T lymphocytes, eosinophils, mast cells, and dendritic cells (figure 3).
Suppression of mucosal inflammation begins within hours of administration [28,29]. As an example, in a double-blind crossover trial, 41 adults with stable asthma and at least 7 percent sputum eosinophilia were randomly assigned to receive a single dose of inhaled budesonide or placebo on two consecutive days [28]. Budesonide decreased sputum eosinophilia within six hours.
Decreased airway inflammation is associated with decreased airway responsiveness, which also begins within hours of inhaled glucocorticoid administration [28-30]. As an example, in three randomized, controlled crossover trials, fluticasone decreased airway responsiveness two- to three-fold within two hours [29]. This effect may gradually increase over several months before reaching a plateau [30].
Nongenomic effects — There is some evidence that glucocorticoids may exert effects on cells independent of binding to GR alpha. These effects, which include alterations in intracellular calcium homeostasis/mobilization and smooth muscle function, may be mediated by cell membrane interactions or by binding to a cell membrane glucocorticoid receptor [27]. Cell culture experiments with transcriptional and GR alpha inhibitors have shown various rapid-acting sequelae of glucocorticoid treatment likely arise from nongenomic mechanisms, but the degree to which these contribute to the in vivo anti-inflammatory actions of glucocorticoids remains poorly defined.
BETA 2-RECEPTOR EFFECTS —
Suppression of airway inflammation is not the only way in which inhaled glucocorticoids reduce the symptoms and signs of asthma. They also enhance beta 2 adrenergic signaling by increasing beta 2-receptor expression and function.
Inhaled beta 2-agonists and glucocorticoids are frequently used together in the management of asthma. Indeed, current guidelines recommend the use of an as-needed combination therapy of an ICS and a rapid-onset long-acting beta-2 agonist as a reliever medication for newly diagnosed asthma. This approach controls airway inflammation and obstruction resulting in improved asthma control and reduced exacerbations with an overall reduction in ICS dosing. (See "An overview of asthma management in children and adults".)
There are also important molecular interactions between these two classes of medication [31,32]. Specifically, glucocorticoids increase transcription of the gene encoding beta 2-receptors, inducing increased expression of beta 2-receptors on the cell surface [33,34]. They also enhance the coupling of beta 2-receptors to G-proteins. Taken together, these actions have the following impact:
●Increased beta 2-agonist effects (eg, mast cell stabilization)
●Protection from the down-regulation of beta 2-receptors that is associated with long-term beta 2-agonist administration [35]
●Reversal or prevention of the uncoupling of beta 2-receptors from G proteins, which is induced by some inflammatory mediators (eg, interleukin 1 beta) [36]
In a reciprocal manner, beta 2-agonists influence the activated glucocorticoid receptors (GR). Specifically, beta 2-agonists increase translocation of the activated GR from the cytoplasm to the nucleus, which enhances the anti-inflammatory effects of glucocorticoids [37]. This has been demonstrated in the sputum macrophages of patients with asthma following administration of an inhaled glucocorticoid plus an inhaled long-acting beta 2-agonist [38].
GLUCOCORTICOID SENSITIVITY —
Some patients (usually with severe asthma) fail to respond to glucocorticoids, both inhaled and systemic. Such "steroid resistant" asthma may be due to reduced anti-inflammatory actions of glucocorticoids, rather than impaired absorption, increased metabolism, or poor compliance. (See "Glucocorticoid resistance in asthma".)
The ratio of GR alpha (which facilitates glucocorticoid action) to GR beta (which inhibits glucocorticoid action) can be altered by changing the expression GR alpha, GR beta, or both. GR beta expression is increased in the cells of asthmatic airways [7]. In glucocorticoid-sensitive cells the ratio tends to be higher, whereas in glucocorticoid-resistant cells the ratio tends to be lower [6]. However, there is little evidence that decreases in the ratio of GR alpha to GR beta reduce glucocorticoid responsiveness because the amount of GR beta is too small to influence GR action. Other molecular mechanisms are more likely to account for glucocorticoid resistance in asthma [39,40]. These include reduced GR nuclear translocation, attenuated or incorrect association with transcriptional cofactors such as HDAC2, or changes in cofactor or GR post-translational modifications [41]. In addition, the presence of T1 inflammation, often induced by airway viral infection, can result in a glucocorticoid refractory state [42,43].
Infection of primary human airway epithelial cells with rhinovirus (RV) results in a steroid-refractory inflammatory response [42]. Importantly, patients with severe asthma with a type 1 (T1) high molecular phenotype have a poor response to the injectable corticosteroid triamcinolone and is linked to a 14-fold greater risk of RV detection in sputum [43]. A high level of T1 inflammation, mainly IFN-gamma and CXCL10, has previously been reported in a subgroup of patients with severe asthma [44-46]. Cooperation between activated GR and STAT1 at the CXCL10 promoter may help drive this persistent T1 drive in these patients [45].
SUMMARY AND RECOMMENDATIONS
●Clinical use – Inhaled glucocorticoids are potent suppressors of inflammation in the airways. They effectively control the symptoms and signs of asthma. (See 'Introduction' above.)
●Molecular effects in the airways – The success of inhaled glucocorticoids in controlling the symptoms and signs of asthma is the net result of many favorable effects in the airways. These effects include:
•Anti-inflammatory gene activation and switching off inflammatory gene expression, which combine to inhibit inflammatory cells infiltration and survival in the airways. (See 'Suppression of inflammation' above.)
•Increased expression of beta 2-receptors and enhanced coupling of beta 2-receptors to G-proteins, which combine to increase beta 2 adrenergic signaling. (See 'Beta 2-receptor effects' above.)
●Glucocorticoid sensitivity – Glucocorticoid-resistant asthma is most commonly due to reduced anti-inflammatory actions of glucocorticoids, rather than impaired absorption, increased metabolism, or poor compliance. (See 'Glucocorticoid sensitivity' above and "Glucocorticoid resistance in asthma".)
