Open AccessAn inhaled dose of budesonide induces genes involved in transcription and signaling in the human airways: enhancement of anti‐ and proinflammatory effector genes
Author(s) -
Leigh Richard,
Mostafa Mahmoud M.,
King Elizabeth M.,
Rider Christopher F.,
Shah Suharsh,
Dumonceaux Curtis,
Traves Suzanne L.,
McWhae Andrew,
Kolisnik Tyler,
Kooi Cora,
Slater Donna M.,
Kelly Margaret M.,
Bieda Mark,
MillerLarsson Anna,
Newton Robert
Publication year - 2016
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.243
Subject(s) - budesonide , proinflammatory cytokine , gene expression , biology , gene , signal transduction , glucocorticoid receptor , immunology , medicine , pharmacology , inflammation , glucocorticoid , microbiology and biotechnology , asthma , genetics
Although inhaled glucocorticoids, or corticosteroids ( ICS ), are generally effective in asthma, understanding their anti‐inflammatory actions in vivo remains incomplete. To characterize glucocorticoid‐induced modulation of gene expression in the human airways, we performed a randomized placebo‐controlled crossover study in healthy male volunteers. Six hours after placebo or budesonide inhalation, whole blood, bronchial brushings, and endobronchial biopsies were collected. Microarray analysis of biopsy RNA , using stringent (≥2‐fold, 5% false discovery rate) or less stringent (≥1.25‐fold, P ≤ 0.05) criteria, identified 46 and 588 budesonide‐induced genes, respectively. Approximately two third of these genes are transcriptional regulators ( KLF 9, PER 1, TSC 22D3, ZBTB 16), receptors ( CD 163, CNR 1, CXCR 4, LIFR , TLR 2), or signaling genes ( DUSP 1, NFKBIA , RGS 1, RGS 2, ZFP 36). Listed genes were qPCR verified. Expression of anti‐inflammatory and other potentially beneficial genes is therefore confirmed and consistent with gene ontology ( GO ) terms for negative regulation of transcription and gene expression. However, GO terms for transcription, signaling, metabolism, proliferation, inflammatory responses, and cell movement were also associated with the budesonide‐induced genes. The most enriched functional cluster indicates positive regulation of proliferation, locomotion, movement, and migration. Moreover, comparison with the budesonide‐induced expression profile in primary human airway epithelial cells shows considerable cell type specificity. In conclusion, increased expression of multiple genes, including the transcriptional repressor, ZBTB 16, that reduce inflammatory signaling and gene expression, occurs in the airways and blood and may contribute to the therapeutic efficacy of ICS . This provides a previously lacking insight into the in vivo effects of ICS and should promote strategies to improve glucocorticoid efficacy in inflammatory diseases.