Abstract
All-trans retinoic acid (ATRA) is an active metabolite of Vitamin A, it shows protective effects on asthma, including maintains airway epithelial integrity, inhibits asthma effector cells differentiation, modulates immune response, et al. However, the promoting effect of ATRA on Th2 response has restricted the clinical application of ATRA in asthma treatment. ORMDL3 is a candidate gene of childhood onset asthma, and high-transcript of ORMDL3 is associated with the development of asthma. Here we show that ATRA increases ORMDL3 production in vitro via inducing PKA-dependent CREB phosphorylation which in turn binds to the CRE element in promoter region of ORMDL3 and initiates ORMDL3 transcription. This finding is in consistent with the previous reports that ATRA could regulate target genes without the presence of retinoic acid response element (RARE) in promoter region but through other signals such as PKA/CREB. Nevertheless, in the present study, the traditional signal pathway of ATRA, retinoic acid receptor (RAR) signal transduction pathway, indirectly modulated ORMDL3 expression. RAR-α agonist (Am-80) increased ORMDL3 production even though there was no RARE in ORMDL3 promoter, introns or 3′-downstream region. Besides, the signal of RAR might differ from that of ATRA since Am-80 failed to induce CREB activation. In conclusion, our data indicate that ATRA facilitates ORMDL3 production probable through PKA/CREB, and this may be a starting point for more detailed mechanism researches on ATRA and asthma.
Highlights
Asthma is a complex trait characterized by airflow obstruction, airway inflammation, and persistent airway hyperreactivity
Since the therapeutic level of All-trans retinoic acid (ATRA) in human plasma is about 1–2 mM [25], we selected the concentration of 1 mM for the time-course examination
retinoic acid (RA) normally activates gene expression through binding to nuclear receptors that interact with retinoic acid response element (RARE) in regulatory regions of target genes
Summary
Asthma is a complex trait characterized by airflow obstruction, airway inflammation, and persistent airway hyperreactivity. It is caused by a combination of genetic predisposition and environmental influences. ORMDL3 was identified as an asthma candidate gene by Genome-wide association studies in diverse human populations [1,2,3,4,5]. ORMDL3 production of airway epithelial cells of mice could be induced by allergen sensitization [9]. These studies indicated that high expression of ORMDL3 might associated with the development of asthma, but the mechanism of ORMDL3 to the pathogenesis of asthma is poorly understood. Functional studies indicated that ORMDL3 is involved in the processes of endoplasmic reticulum stress induction [10], sphingolipid regulation [11] and T-lymphocyte activation [12]
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