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Expression profiling identifies Klf15 as a glucocorticoid target that regulates airway hyperresponsiveness
Kiriko Masuno1, Saptarsi M Haldar, Darwin Jeyaraj
1Department of Molecular and Cellular Pharmacology, University of California, San Francisco, California, USA.
Glucocorticoids (GCs) regulate genes impacting airway smooth muscle function in asthma. A novel GC-regulated gene, Kruppel-like factor 15 (Klf15), controls airway responses and smooth muscle cell proliferation.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Genetics
Background:
- Glucocorticoids (GCs) are primary asthma treatments, modulating airway smooth muscle (ASM) function via GC receptor (GR) signaling.
- The specific genes regulated by GCs and their impact on ASM function remain incompletely understood.
Purpose of the Study:
- To investigate the gene expression changes induced by dexamethasone in human ASM (HASM) cells.
- To identify novel GR-regulated genes and elucidate their role in airway smooth muscle function and asthma.
Main Methods:
- Transcription profiling of HASM cells treated with dexamethasone for 4 and 24 hours.
- Quantitative PCR validation of GR-regulated genes.
- Analysis of Kruppel-like factor 15 (Klf15) knockout mouse models in an asthma model.
- Cell proliferation and apoptosis assays in HASM and murine ASM cells.
Main Results:
- Dexamethasone significantly altered the expression of thousands of genes in HASM cells after 24 hours.
- Early GR transcriptional targets were consistent across independent HASM cell lines.
- Klf15 deficiency in mice led to diminished airway hyperresponsiveness without altering inflammation.
- Klf15 overexpression reduced HASM cell proliferation, while Klf15 deficiency increased ASM cell apoptosis.
Conclusions:
- GCs regulate a broad network of genes impacting ASM function.
- Klf15 is a novel GR target gene that plays a critical role in modulating airway smooth muscle cell proliferation, apoptosis, and airway hyperresponsiveness.
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