IL-4 plays an important role in the pathogenesis of atopic dermatitis (AD) by dysregulating many key factors at the transcriptional level. In this study, a microRNA array technique and IL-4 transgenic mice were used to demonstrate that IL-4 dysregulates microRNAs involved in inflammation, angiogenesis, lymphangiogenesis and apoptosis. Of the 372 common microRNAs examined, 26 and one microRNAs were found to be up-and down-regulated, respectively. MicroRNA-101-5p, À122-5p, À142-3p, À204-5p, À335-3p, À376a-3p, À378a-5p, À639 and À9-5p are among the most significantly up-regulated microRNAs. MicroRN A-147a, the only one that was down-regulated in the present study, attenuates TLR-induced inflammatory responses. These dysregulated microRNAs may provide post-transcriptional regulation of key genes in AD.
Purinergic signaling is crucial to maintain homeostasis of inflammation. We previously elucidated that disruption of homeostasis of skin inflammation by Zn deficiency-mediated ablation of Langerhans cells (LC) that expressed CD39 was causative for dermatitis in acrodermatitis enteropathica. ATP was hydrolyzed into AMP by E-NTPDases (Entpd), E-NPPs (Enpp), and tissue non-specific alkaline phosphatases (TNAP). LC express Entpd1 (CD39) and keratinocytes (KC) do not express it. However, the expression of other ATP-hydrolyzing molecules in LC and KC is not addressed. The purpose of this study is 1. to determine the expression of these ATP-hydrolyzing molecules in LC and KC by qPCR, and 2. to examine the alteration of expression of these ATP-hydrolyzing molecules under Zn deficient condition. Normal murine KC expressed Entpd2, Enpp1, and low levels of Enpp2 and TNAP, whereas normal human epidermal KC expressed Entpd2, Entpd3, and Enpp1. Normal murine LC expressed Entpd1 (CD39), Entpd2, and low level of Enpp1, whereas normal human LC expressed Entpd1 (CD39), and low levels of Enpp2 and Enpp3. KC from Zn-deficient diet mice showed increased expression of Entpd2 and Enpp1, and loss of expression of Enpp2 and TNAP. Finally, we examined the impact of LC in ATP hydrolysis. ATP hydrolysis activity was determined by measuring released phosphate. ATP hydrolysis activity was impaired up to 82% in LC-depleted murine epidermis compared with LC-existing murine epidermis. These data suggested that the expression of ATP-hydrolyzing molecules in LC and KC were different between mice and humans. Additionally, Zn deficiency altered the expression of ATPhydrolyzing molecules in KC. Lastly, Entpd1 (CD39)-and Entpd2-expressing LC assumed about 80% of ATP hydrolysis, whereas Entpd2-and Enpp1-expressing KC assumed the remaining 20% ATP hydrolysis in murine epidermis.
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