PMID- 34775963 OWN - NLM STAT- MEDLINE DCOM- 20220311 LR - 20220531 IS - 1743-422X (Electronic) IS - 1743-422X (Linking) VI - 18 IP - 1 DP - 2021 Nov 14 TI - Neutralization of interleukin-38 exacerbates coxsackievirus B3-induced acute myocarditis in mice. PG - 220 LID - 10.1186/s12985-021-01687-w [doi] LID - 220 AB - BACKGROUND: Interleukin (IL)-38, a novel member of the IL-1 family, has been reported to be involved in several diseases associated with viral infection. However, the expression and functional role of IL-38 in acute viral myocarditis (AVMC) have not been investigated. METHODS: Male BALB/c mice were treated with intraperitoneal (i.p.) injection of coxsackievirus B3 (CVB3) for establishing AVMC models. On day 7 post-injection, the expression of IL-38 and IL-36R (IL-36 receptor) were measured. Mice were then treated with i.p. injection of mouse Anti-IL-38 Antibodies (Abs) for neutralization of IL-38. The survival, bodyweight loss, cardiac function, and myocarditis severity of mice were recorded. The percentages of splenic Th1 and Th17 cells, the expression levels of Th1/Th17-related master transcription factors (T-bet and RORgammat) and cytokines were determined by flow cytometry, RT-qPCR, and ELISA, respectively. Cardiac viral replication was further detected. RESULTS: The mRNA and protein expression levels of IL-38 in myocardium and serum, as well as cardiac IL-36R mRNA levels were significantly elevated in mice with AVMC. Increased IL-38 levels were negatively correlated with the severity of AVMC. Neutralization of IL-38 exacerbated CVB3-induced AVMC, as verified by the lower survival rate, impaired cardiac function, continuous bodyweight loss, and higher values of HW/BW and cardiac pathological scores. In addition, neutralization of IL-38 suppressed Th1 cells differentiation while promoted Th17 cells differentiation, accompanied by decreased T-bet mRNA expression and increased RORgammat expression. Down-regulation of IFN-gamma and up-regulation of IL-17, TNF-alpha, and IL-6 mRNA and protein expression levels in myocardium and serum were also observed in the IL-38 neutralization group. Furthermore, neutralization of IL-38 markedly promoted cardiac viral replication. CONCLUSIONS: Neutralization of IL-38 exacerbates CVB3-induced AVMC in mice, which may be attributable to the imbalance of Th1/Th17 cells and increased CVB3 replication. Thus, IL-38 can be considered as a potential therapeutic target for AVMC. CI - (c) 2021. The Author(s). FAU - Xue, Yimin AU - Xue Y AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, People's Republic of China. AD - The Fourth Department of Intensive Care Unit, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, People's Republic of China. AD - Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, 350001, Fujian, People's Republic of China. FAU - Chen, Mingguang AU - Chen M AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, People's Republic of China. AD - The Fourth Department of Intensive Care Unit, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, People's Republic of China. FAU - Chen, Qian AU - Chen Q AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, People's Republic of China. AD - The Fourth Department of Intensive Care Unit, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, People's Republic of China. FAU - Huang, Tingfeng AU - Huang T AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, People's Republic of China. AD - The Fourth Department of Intensive Care Unit, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, People's Republic of China. FAU - Fan, Qiaolian AU - Fan Q AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, People's Republic of China. AD - The Fourth Department of Intensive Care Unit, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, People's Republic of China. FAU - Lin, Fenghui AU - Lin F AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, People's Republic of China. AD - The Fourth Department of Intensive Care Unit, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, People's Republic of China. FAU - Ke, Jun AU - Ke J AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, People's Republic of China. AD - Department of Emergency, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, People's Republic of China. AD - Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, 350001, Fujian, People's Republic of China. FAU - Chen, Feng AU - Chen F AUID- ORCID: 0000-0002-4419-9707 AD - Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, People's Republic of China. fjslchenfeng@126.com. AD - Department of Emergency, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, People's Republic of China. fjslchenfeng@126.com. AD - Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, 350001, Fujian, People's Republic of China. fjslchenfeng@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211114 PL - England TA - Virol J JT - Virology journal JID - 101231645 RN - 0 (Antibodies, Neutralizing) RN - 0 (Il1f10 protein, mouse) RN - 0 (Interleukin-1) SB - IM MH - Animals MH - Antibodies, Neutralizing MH - *Coxsackievirus Infections/metabolism MH - Enterovirus B, Human/physiology MH - *Interleukin-1/metabolism MH - Male MH - Mice MH - Mice, Inbred BALB C MH - *Myocarditis/metabolism/virology MH - Myocardium/pathology MH - Th17 Cells PMC - PMC8590870 OTO - NOTNLM OT - Acute viral myocarditis OT - Coxsackievirus B3 OT - IL-38 OT - Th1 cells OT - Th17 cells COIS- The authors declare that they have no competing interests. EDAT- 2021/11/16 06:00 MHDA- 2022/03/12 06:00 PMCR- 2021/11/14 CRDT- 2021/11/15 05:39 PHST- 2021/07/05 00:00 [received] PHST- 2021/11/01 00:00 [accepted] PHST- 2021/11/15 05:39 [entrez] PHST- 2021/11/16 06:00 [pubmed] PHST- 2022/03/12 06:00 [medline] PHST- 2021/11/14 00:00 [pmc-release] AID - 10.1186/s12985-021-01687-w [pii] AID - 1687 [pii] AID - 10.1186/s12985-021-01687-w [doi] PST - epublish SO - Virol J. 2021 Nov 14;18(1):220. doi: 10.1186/s12985-021-01687-w.