Enhancement of inflammatory mediator release by β₂‐adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action

Abstract

Background and purpose: Due to their potent bronchodilator properties, b2-adrenoceptor agonists are a mainstay of therapy in asthma. However, the effects of b2-adrenoceptor agonists on inflammation are less clear. Accordingly, we have investigated the effects of b2-adrenoceptor agonists on inflammatory mediator release. Experimental approach: Transcription factor activation, and both release and mRNA expression of IL-6 and IL-8 were examined by luciferase reporter assay, ELISA and real-time RT-PCR in bronchial human epithelial BEAS-2B cells or primary human bronchial epithelial cells grown at an air-liquid interface. Key results: Pre-incubation with b2-adrenoceptor agonists (salbutamol, salmeterol, formoterol) augmented the release and mRNA expression of IL-6 and IL-8 induced by IL-1b and IL-1b plus histamine, whereas NF-kB-dependent transcription was significantly repressed, and AP-1-dependent transcription was unaffected. These effects were mimicked by other cAMPelevating agents (PGE2, forskolin). Enhancement of cytokine release by b2-adrenoceptor agonists also occurred in primary bronchial epithelial cells. Addition of dexamethasone with salmeterol repressed IL-6 and IL-8 release to levels that were similar to the repression achieved in the absence of salmeterol. IL-6 release was enhanced when salmeterol was added before, concurrently or after IL-1b plus histamine stimulation, whereas IL-8 release was only enhanced by salmeterol addition prior to stimulation. Conclusions and implications:Enhancement of IL-6 and IL-8 release may contribute to the deleterious effects of b2-adrenoceptor agonists in asthma. As increased inflammatory mediator expression is prevented by the addition of glucocorticoid to the b2-adrenoceptor, our data provide further mechanistic support for the use of combination therapies in asthma management.

Phosphodiesterase 4 Inhibitors Augment the Ability of Formoterol to Enhance Glucocorticoid-Dependent Gene Transcription in Human Airway Epithelial Cells: A Novel Mechanism for the Clinical Efficacy of Roflumilast in Severe Chronic Obstructive Pulmonary Disease

“…In addition (although not examined here), a LABA and/or PDE4 inhibitor may upregulate cAMP-inducible, antiinflammatory genes that are insensitive to glucocorticoids, which could contribute to the therapeutic activity of roflumilast reported in COPD patients not taking ICS (Calverley et al, 2009). In concluding, it is appropriate to acknowledge that, although LABAs and PDE4 inhibitors alone can induce a variety of proinflammatory genes, this unwanted effect could be mitigated by an ICS and may not be overly problematic (Hertz et al, 2009;Holden et al, 2010). Thus, in severe COPD, the clinical efficacy of an ICS, a LABA, and a PDE4 inhibitor in combination may be attributable, in part, to their collective actions on gene transcription (Giembycz and Newton, 2011).…”

Concurrent Agonism of Adenosine A2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

“…However, while the therapeutic implications of this undesirable property needs to be more fully evaluated, it may not be problematic given that many of these cAMP-inducible genes are repressed by glucocorticoids (Holden et al, 2010;King et al, 2013). Thus in COPD, which is generally refractory to glucocorticoids as a monotherapy, clinical efficacy may be Fig.…”

“…One final concern of adenosine A 2B -receptor agonists is their ability to up-regulate the expression of certain proinflammatory genes (e.g., IL6, IL19, and CCL2; Zhong et al, 2004Zhong et al, , 2006, which is typical of drugs that elevate cAMP, including b 2 -adrenoceptor agonists (Holden et al, 2010). However, while the therapeutic implications of this undesirable property needs to be more fully evaluated, it may not be problematic given that many of these cAMP-inducible genes are repressed by glucocorticoids (Holden et al, 2010;King et al, 2013).…”

Superiority of Combined Phosphodiesterase PDE3/PDE4 Inhibition over PDE4 Inhibition Alone on Glucocorticoid- and Long-Acting β2-Adrenoceptor Agonist–Induced Gene Expression in Human Airway Epithelial Cells

“…Conversely, b 2 -adrenoceptor agonists elicit various proinflammatory responses, such as the enhancement of interleukin-8 release (Holden et al, 2010), which are inhibited by glucocorticoids (Giembycz and Newton, 2006;Newton et al, 2010). Although glucocorticoid/LABA combinations may show enhanced repression of inflammatory gene expression (Edwards et al, 2006), evidence for functional synergy on inflammatory outputs is less common (Pang and Knox, 2000), with most studies showing additivity (Pang and Knox, 2001;Newton et al, 2010).…”