Distinct Th17 inductions contribute to the gender bias in CVB3-induced myocarditis

Background: Viral myocarditis is often caused by coxsackievirus B3 (CVB3) infection and occurs more frequently in males. So far, the mechanisms for this sex difference are not fully elucidated. As a new proinflammatory T cell population, Th17 cells are required for the development of CVB3-induced myocarditis, but their impact on the gender bias in viral myocarditis is still unknown. Methods: Male and female mice were intraperitoneally infected with CVB3; 7 days later, the frequency of splenic Th17 cells and the expression of associated cytokines and transcriptional factors were compared. Meanwhile, the impact of sex hormones on Th17 cell differentiation post CVB3 infection was also evaluated. Results: In infected male mice, Th17 cell frequency was remarkably increased and significantly higher than that in female mice. Accordingly, the expression of associated cytokines and transcriptional factors was also obviously augmented in males. When neutralizing interleukin-17 by monoclonal antibody, the male prevalence of myocarditis was obviously abolished, further confirming the effect of Th17 cells on gender bias in viral myocarditis. It was also found that estradiol significantly inhibited the Th17 differentiation post CVB3 infection both in vitro and in vivo. However, testosterone showed no such effects. Conclusions: Th17 cells were predominantly induced in CVB3-infected males than females as the inhibitory effect of estrogen on Th17 differentiation and played an important role in the sex differences in the sensitivity to CVB3-induced myocarditis. This study may help us understand the role of Th17 cells in viral myocarditis and facilitate the development of corresponding therapeutic strategies. (c) 2013 Elsevier Inc. All rights reserved.