{Reference Type}: Journal Article
{Title}: CEBPD modulates the airway smooth muscle transcriptomic response to glucocorticoids.
{Author}: Kan M;Sun M;Jiang X;Diwadkar AR;Parikh V;Cao G;Gebski E;Jester W;Lan B;Panettieri RA;Koziol-White C;Lu Q;Himes BE;
{Journal}: Respir Res
{Volume}: 23
{Issue}: 1
{Year}: Jul 2022 28
暂无{DOI}: 10.1186/s12931-022-02119-1
{Abstract}: <B>BACKGROUND: </B>CCAAT/Enhancer Binding Protein D (CEBPD), a pleiotropic glucocorticoid-responsive transcription factor, modulates inflammatory responses. Of relevance to asthma, expression of CEBPD in airway smooth muscle (ASM) increases with glucocorticoid exposure. We sought to characterize CEBPD-mediated transcriptomic responses to glucocorticoid exposure in ASM by measuring changes observed after knockdown of CEBPD and its impact on asthma-related ASM function.<BR><B>METHODS: </B>Primary ASM cells derived from four donors were transfected with CEBPD or non-targeting (NT) siRNA and exposed to vehicle control, budesonide (100 nM, 18 h), TNFα (10 ng/ml, 18 h), or both budesonide and TNFα. Subsequently, RNA-Seq was used to measure gene expression levels, and pairwise differential expression results were obtained for exposures versus vehicle and knockdown versus control conditions. Weighted gene co-expression analysis was performed to identify groups of genes with similar expression patterns across the various experimental conditions (i.e., CEBPD knockdown status, exposures).<BR><B>RESULTS: </B>CEBPD knockdown altered expression of 3037 genes under at least one exposure (q-value < 0.05). Co-expression analysis identified sets of 197, 152 and 290 genes that were correlated with CEBPD knockdown status, TNFα exposure status, and both, respectively. JAK-STAT signaling pathway genes, including IL6R and SOCS3, were among those influenced by both TNFα and CEBPD knockdown. Immunoblot assays revealed that budesonide-induced IL-6R protein expression and augmented IL-6-induced STAT3 phosphorylation levels were attenuated by CEBPD knockdown in ASM.<BR><B>CONCLUSIONS: </B>CEBPD modulates glucocorticoid responses in ASM, in part via modulation of IL-6 receptor signaling.