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bioRxiv · 10.1101/2020.01.23.916890

Interleukin-35 pretreatment attenuates lipopolysaccharide-induced heart injury by inhibition of inflammation, apoptosis and fibrosis

Fu, Y.·Hu, H.·Li, M.·Xia, H.·Liu, Y.·Sun, X.·Hu, Y.·Song, F.·Cheng, X.·Li, P.·Wu, Y.
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Abstract

Previous studies have demonstrated that targeting inflammation is a promising strategy for treating lipopolysaccharide (LPS)-induced sepsis and related heart injury. Interleukin-35 (IL-35), which consists of two subunits, Epstein-Barr virus-induced gene 3 (EBI3) and p35, is an immunosuppressive cytokine of the IL-12 family and exhibits strong anti-inflammatory activity. However, the role of IL-35 in LPS-induced heart injury remains obscure. In this study, we explored the role of IL-35 in heart injury induced by LPS and its potential mechanisms. Mice were treated with a plasmid encoding IL-35 (pIL-35) and then injected intraperitoneally (ip) with LPS (10 mg/kg). Cardiac function was assessed by echocardiography 12 h later. LPS apparently decreased the expression of EBI3 and p35 and caused cardiac dysfunction and pathological changes, which were significantly improved by pIL-35 pretreatment. Moreover, pIL-35 pretreatment significantly decreased the levels of cardiac proinflammatory cytokines including TNF-, IL-6, and IL-1{beta}, and the NLRP3 inflammasome. Furthermore, increased BCL-2 levels and decreased BAX levels inhibited apoptosis, and LPS-induced upregulation of the expression of pro-fibrotic genes (MMP2 and MMP9) was inhibited. Further investigation indicated that pIL-35 pretreatment suppressed the activation of the cardiac NF-{kappa}Bp65 and TGF-{beta}1/Smad2/3 signaling pathways in LPS-treated mice. Similar cardioprotective effects of IL-35 pretreatment were observed in mouse myocardial fibroblasts challenged with LPS in vitro. In summary, IL-35 pretreatment can attenuate cardiac inflammation, apoptosis, and fibrosis induced by LPS, implicating IL-35 as a promising therapeutic target in sepsis-related cardiac injury.

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Fu, Y., Hu, H., Li, M., Xia, H., Liu, Y., Sun, X., Hu, Y., Song, F., Cheng, X., Li, P., Wu, Y.. 2020-01-24. Interleukin-35 pretreatment attenuates lipopolysaccharide-induced heart injury by inhibition of inflammation, apoptosis and fibrosis. https://doi.org/10.1101/2020.01.23.916890

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