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Phosphodiester CpG-ODN ameliorates atopic dermatitis by enhancing TGF-モ signaling
WonKook Ham1 (Graduate student), EunJung Lee1 (Research worker), MyungShin Jeon2 (Professor), HaeYoung Kim 1 (Research worker), Gaurav Agrahari 1 (Research worker), Eun-Joo An 1 (Research worker), Chul Hwan Bang 1 (Research worker), Doo-Sik Kim3 (Research worker), TaeYoon Kim 1,* (Professor)
1Department of Dermatology, College of Medicine, The Catholic University of Korea,
2Department of Molecular Biomedicine, College of Medicine, Inha University,
3Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University
Abstract
Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG phosphorothioate (PS CpG-ODN) are known to decrease IgE synthesis in Th2 allergy responses. Despite of this beneficial effect, PS CpG-ODN treatment in patients are limited due to cytotoxicity. Therefore, we developed phosphodiester (PO) form of CpG-ODN (46O), which is effective against allergies and exhibits low toxicity. In this study, we first compared the toxicity of 46O with CpG-ODNs with a PS backbone (1826S) and also investigated the therapeutic efficacy and mechanism of 46O in ovalbumin (OVA)-induced atopic dermatitis (AD). In a mouse model of OVA-induced AD, 46O was injected intravenously. To understand the underlying mechanism of 46O on inhibiting IgE production, IgE- and TGF-モ-associated molecules were evaluated in CD40/IL-4- or LPS/IL-4-stimulated B cells. Our data showed that, treatment with 46O showed lower hematological toxicity compared to 1826S. In addition, injection with 46O exhibited reduced erythema, epidermal thickness, and suppressed IgE and IL-4 productions in mice with OVA-induced AD. Additionally, 46O induced TGF-モ production in LPS/IL-4-stimulated B cells through inhibition of Smad7, which suppressed IgE production by inducing interaction between Id2 and E2A. These findings suggest that enhancement of TGF-モ signaling is an effective approach for treating IgE-mediated allergic conditions, and 46O may be a safe and useful candidate for treating allergic diseases such as AD and asthma.
Abstract, Accepted Manuscript(in press) [Submitted on November 13, 2020, Accepted on January 4, 2021]
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