期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 303, 期 5, 页码 L460-L468出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00041.2012
关键词
asthma; gene expression; microRNA
资金
- National Institutes of Health [HL-057498, ES-013508, HL-097796]
- Academic Health Center at the University of Minnesota
- Comparative Medicine Signature Program of the College of Veterinary Medicine, University of Minnesota
Jude JA, Dileepan M, Subramanian S, Solway J, Panettieri RA Jr, Walseth TF, Kannan MS. miR-140-3p regulation of TNF-alpha-induced CD38 expression in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 303: L460-L468, 2012. First published July 6, 2012; doi:10.1152/ajplung.00041.2012.-CD38, a membrane protein expressed in airway smooth muscle (ASM) cells, plays a role in cellular Ca2+ dynamics and ASM contractility. In human ASM (HASM) cells, TNF-alpha induces CD38 expression through activation of MAPKs, NF-kappa B, and AP-1, and its expression is differentially elevated in cells from asthmatic patients compared with cells from nonasthmatic subjects. The CD38 3'-untranslated region (UTR) has targets for miR-140-3p. We hypothesized that miR-140-3p regulates CD38 expression in HASM cells by altering CD38 mRNA stability. Basal and TNF-alpha-induced expression of miR-140-3p was determined in nonasthmatic ASM (NAASM) and asthmatic ASM (AASM) cells. NAASM and AASM cells were transfected with control, miR-140-3p mimic, or miR-140-3p antagomirs, and CD38 expression and CD38 mRNA stability were determined. Luciferase reporter assays were used to determine miR-140-3p binding to the CD38 3'-UTR. Activation of p38, ERK, and JNK MAPKs, NF-kappa B, and AP-1 was determined in miR-140-3p mimic-transfected NAASM. TNF-alpha attenuated miR-140-3p expression in NAASM and AASM cells, but at a greater magnitude in AASM cells. CD38 mRNA expression was attenuated by miR-140-3p mimic at comparable magnitude in NAASM and AASM cells. Mutated miR-140-3p target on the CD38 3'-UTR reversed the inhibition of luciferase activity by miR-140-3p mimic. CD38 mRNA stability was unaltered by miR-140-3p mimic in NAASM or AASM cells following arrest of transcription. TNF-alpha-induced activation of p38 MAPK and NF-kappa B was attenuated by miR-140-3p mimic. The findings indicate that miR-140-3p modulates CD38 expression in HASM cells through direct binding to the CD38 3'-UTR and indirect mechanisms involving activation of p38 MAPK and NF-kappa B. Furthermore, indirect mechanisms appear to play a major role in the regulation of CD38 expression.
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