Published ahead of print on June 29, 2006, doi:10.1165/rcmb.2006-0073OC Am. J. Respir. Cell Mol. Biol., Volume 35, Number 6, December 2006, 668-680 A more recent version of this article appeared on December 1, 2006
Submitted on February 16, 2006 Importin 13 Regulates Nuclear Import of the Glucocorticoid Receptor in Airway Epithelial CellsTao Tao1,1 McGill University-Montreal Children's Hospital Research Institute, Montreal, QC, Canada, 2 The Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada, 3 The Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada, 4 McGill University-Montreal Children's Hospital Research Institute, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Pediatrics, McGill University, Montreal, QC, Canada * To whom correspondence should be addressed. E-mail: feige.kaplan{at}mcgill.ca.
Anti-inflammatory effects of glucocorticoids are critical to treatment of airway inflammation in such common disorders as asthma. There is considerable variation in responsiveness to glucocorticoid and prolonged exposure can result in glucocorticoid resistance. We cloned LGL2, a glucocorticoid-inducible gene in fetal rat lung. We described the characterization of lgl2 as a nuclear transport protein, classified as importin 13 (IPO13), and demonstrated developmental regulation of IPO13 nucleocytoplasmic shuttling. We now report on the identification of the glucocorticoid receptor (GR) as a cargo substrate for IPO13. Binding of GR and IPO13 was demonstrated by GR-GST pulldown and coimmunoprecipitation. To investigate the role of IPO13 in modulating GR signaling in the lung, we studied IPO13 regulated GR transport in airway epithelial cells. Small interfering RNAs that inhibited IPO13 synthesis prevented nuclear translocation of GR. Silencing of IPO13 also abrogated the ability of cortisol to inhibit synthesis of the inflammatory cytokine interleukin-8 following stimulation with TNF-
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. Our findings support a role for IPO13 in promoting nuclear occupancy of GR in a way that strongly potentiates the anti-inflammatory effects of glucocorticoids. We speculate that variation in cellular levels of IPO13 and intracellular IPO13 shuttling rates may contribute to glucocorticoid resistance.