title: Valproic acid ameliorates coxsackievirus-B3-induced viral myocarditis by modulating Th17/Treg imbalance.
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.
authors.affiliation: Department of Geria Care, 254th Hospital of PLA, No 60 Huangwei Road, Tianjin, 300142, China. hbjin_090@sina.com.
authors.forename: Haibin
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Geria Care, 254th Hospital of PLA, No 60 Huangwei Road, Tianjin, 300142, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Guo
mesh_terms: D000818:Animals; D001835:Body Weight; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000302:isolation & purification*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007155:Immunologic Factors / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008297:Male; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D014635:Valproic Acid
keywords: Th17 cells; Treg cells; Valproic acid; Viral myocarditis