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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Animals
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Asthma / genetics
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Asthma / metabolism
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Asthma / pathology
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Benzoates / pharmacology
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Cell Differentiation
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Cell Line, Tumor
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Cyclic AMP Response Element-Binding Protein / genetics*
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclic AMP-Dependent Protein Kinases / genetics*
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Epithelial Cells / cytology
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Gene Expression Regulation*
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Humans
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Introns
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mice
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NIH 3T3 Cells
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Phosphorylation
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Receptors, Retinoic Acid / agonists
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Receptors, Retinoic Acid / genetics*
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Receptors, Retinoic Acid / metabolism
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Response Elements
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Retinoic Acid Receptor alpha
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Signal Transduction
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Tetrahydronaphthalenes / pharmacology
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Transcription, Genetic
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Tretinoin / metabolism
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Tretinoin / pharmacology*
Substances
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3' Untranslated Regions
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Benzoates
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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Membrane Proteins
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ORMDL3 protein, human
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RARA protein, human
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Rara protein, mouse
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Tetrahydronaphthalenes
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tamibarotene
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Tretinoin
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Cyclic AMP-Dependent Protein Kinases
Grants and funding
This work was supported by the National Natural Science Foundation of China (30872804 and 81170661 to GPZ, 81300023 to RJ), Specialized Research Fund for the Doctoral Program of Higher Education (20113234110010 to GPZ), the Jiangsu Province Innovation Project for Graduate Student of China (CXZZ11_0714 to LLZ) and the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.