Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids

*Division of Pulmonary and Critical Care Medicine and
**Lung Biology Center, Department of Medicine,
^†Cardiovascular Research Institute, and
^‖Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143;
^§The J. David Gladstone Institutes, San Francisco, CA 94158;
^‡Department of Medicine, Stanford University, Palo Alto, CA 94305; and
^¶School of Mathematics and Statistics, University of Sydney, Sydney NSW 2006, Australia

Contributed by Keith R. Yamamoto, August 15, 2007 (received for review April 19, 2007)

Abstract

Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial–mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.

Footnotes

^††To whom correspondence may be addressed at:
University of California at San Francisco, Box 2280, Genentech Hall S572D, 600 16th Street, San Francisco, CA 94158-2517.
E-mail: yamamoto{at}cmp.ucsf.edu
^‡‡To whom correspondence may be addressed at:
University of California at San Francisco, Box 0130, 505 Parnassus Avenue, San Francisco, CA 94143.
E-mail: john.fahy{at}ucsf.edu
Author contributions: P.G.W., G.M.D., C.S.B., C.P., D.J.E., K.R.Y., and J.V.F. designed research; P.G.W., H.A.B., S.D., A.E., S.S.S., T.P.D.-P., C.P., and J.V.F. performed research; G.M.D., C.S.B., and Y.H.Y. contributed new reagents/analytic tools; P.G.W., C.S.B., Y.H.Y., C.P., D.J.E., K.R.Y., and J.V.F. analyzed data; and P.G.W., H.A.B., S.S.S., D.J.E., K.R.Y., and J.V.F. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The microarray data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE4302).
This article contains supporting information online at www.pnas.org/cgi/content/full/0707413104/DC1.
↵ §§ The clinical trial registration information is as follows: ClinicalTrials.gov identifier NCT00187499; study ID nos. H6788-20160-04; P50HL56385; last updated December 8, 2005; record first received September 13, 2005.
Abbreviations:

qPCR,

quantitative real-time PCR;

FKBP51,

FK506-binding protein 51;

GR,

glucocorticoid receptor;

ALI,

air–liquid interface.