Valproic acid ameliorates coxsackievirus-B3-induced viral myocarditis by modulating Th17/Treg imbalance
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RESEARCH
Open Access
Valproic acid ameliorates coxsackievirus-B3induced viral myocarditis by modulating Th17/Treg imbalance Haibin Jin* and Xiaoming Guo
Abstract Background: Viral myocarditis, which is often caused by coxsackievirus B3 (CVB3), is a serious clinical disorder characterized by excessive myocardial inflammation. Valproic acid (VPA) is described as a histone deacetylase inhibitor that has anti-inflammatory effects in several inflammatory diseases. However, the role and the detailed mechanism of VPA in viral myocarditis remain unclear. Methods: Experimental CVB3-induced myocarditis was induced in mice by intraperitoneally (i.p.) infected with CVB3. VPA was i.p. administered from day 0 to day 7. The survival, body weight loss, and myocarditis severity of mice were recorded. Th17 and Treg cells in spleen were analyzed by flow cytometry. Th17/Treg cell-related cytokine expressions were quantified by ELISA. The effect of VPA on Th17 and Treg cells differentiation was examined in vitro and in vivo. Results: Administration of VPA significantly attenuated the clinical severity of myocarditis, and the overall mortality from CVB3-induced myocarditis. The infiltration of Th17 and Treg cells, as well as the serum level of related cytokines (IL-17A and IL-10), were increased in CVB3 infected mice. In addition, VPA decreased the percentage of splenic Th17 cells while increased the percentage of Treg cells. Moreover, VPA downregulated the expression of IL-17A and upregulated IL-10 in serum and heart tissues of CVB3 infected mice. Additionally, VPA directly inhibited the differentiation of Th17 cells and promoted both the differentiation and suppressive function of Treg cells in vitro and in vivo. Conclusions: Our results suggest that VPA may thus be a promising strategy in the therapy of viral myocarditis. Keywords: Viral myocarditis, Valproic acid, Th17 cells, Treg cells
Background Viral myocarditis, which is often caused by coxsackievirus B3 (CVB3)-triggered myocarditis, is one of the leading causes of severe heart failure, and even sudden death in young adults [1]. Viral myocarditis is an immune-mediated disease characterized by inflammatory infiltration of the myocardium and cardiac myocyte necrosis [2, 3]. It has been shown that several T helper (Th) subsets, such as Th17 and Treg cells, are involved in the pathogenesis of viral myocarditis [4–6]. Th17 cells are a new subset of CD4+ T cells that secrete the characteristic cytokine interleukin-17A (IL-17A). There is also * Correspondence: [email protected] Department of Geria Care, 254th Hospital of PLA, No 60 Huangwei Road, Tianjin 300142, China
evidence that Th17 cells contribute to myocarditis development and pathogenesis [4, 5, 7]. Treg cells characteristically express the transcription factor forkhead box P3 (Foxp3), secrete anti-inflammatory cytokines such as IL-10 and transforming growth factor-β (TGF-β), and act to maintain immune homeostasis and control immune-mediated tissue injury. Treg cells are also involved in inflammation and tissue destructio
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