Abstract
BackgroundGlucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20).Methods10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association.ResultsAmong participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51–2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01–0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids.ConclusionIPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.
Highlights
Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells
We report that IPO13 variants differentially influenced airway hyperresponsiveness by treatment group, with improvements in AHR noted among subjects who were randomized to either placebo or nedocromil to levels similar to subjects who were randomized to budesonide, suggesting that common IPO13 variants may increase the nuclear bioavailability of endogenous GCs
We have demonstrated that genetic variation in IPO13 is associated with reduced airway hyperresponsiveness among children with mild-to-moderate asthma who are
Summary
Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. As a result of their potent anti-inflammatory properties, exogenous GCs serve as the most commonly used treatment for the long-term control of asthma[5] by effectively reducing airway hyperresponsiveness (AHR) and asthma symptoms[6], preventing exacerbations[7], and reducing asthma-associated mortality[8]. To access its genomic targets, GC-GR complexes must first pass from the cytoplasm to the nucleus through nuclear pore complexes. This process of GC- receptor shuttling across the nuclear-cytoplasmic membrane is tightly regulated by the interaction of cell-specific nuclear transport factors with cognate nuclear localization sequences[11]. We (FK) demonstrated that IPO13 silencing prevents GC transport across the cytoplasmic-nuclear membrane in airway epithelium and abrogates GC-induced anti-inflammatory responses, suggesting that IPO13 is a critical nuclear transporter of GC receptor in the airway epithelium[13]
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