A20 (TNFAIP3) alleviates CVB3-induced myocarditis via inhibiting NF-κB signaling.
A20 (TNFAIP3) alleviates CVB3-induced myocarditis via inhibiting NF-κB signaling.
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DOI：
10.1371/journal.pone.0046515
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Xiong S
中科院分区：
文献类型：
--
作者：
Gui J;Yue Y;Chen R;Xu W;Xiong S
病毒性心肌炎是由柯萨奇B3病毒(CVB3)感染引起的以心脏炎症为特征的严重临床疾病。然而，针对炎症的有效疗法仍然缺乏，迫切需要。A20，也被称为肿瘤坏死因子α诱导蛋白3(TNFAIP3)，是一种关键的炎症负性调节因子。但A20是否可能影响急性病毒性心肌炎期间的心脏炎症仍有待阐明。本研究的目的是探讨A20对CVB3诱导的心肌炎的潜在保护作用。小鼠腹腔接种CVB3建立急性病毒性心肌炎模型。结果发现，致炎细胞因子肿瘤坏死因子-α、白介素1-α、白介素6、单核细胞趋化蛋白-1的表达在CVB3型心肌炎的发病过程中持续显著升高，且与病情严重程度呈正相关。值得注意的是，体内静脉注射腺病毒表达A20(Ad-A20)显著减少了CVB3诱导的促炎细胞因子的产生，并减轻了心肌炎的严重程度。此外，我们观察到，在用Ad-A20治疗CVB3感染的小鼠中，介导炎症反应的核因子-kappaB(NF-κB)信号显著受到抑制。最后，我们发现A20通过限制κ受体相关因子6的泛素化来抑制CVB3诱导的NF-TRAFB信号转导。本研究证实了A20对CVB3所致心肌炎的保护作用，为治疗病毒性心肌炎提供了一种新的治疗策略。
Viral myocarditis, which is most prevalently caused by Coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. However, efficient therapies targeting inflammation are still lacking and much needed. A20, also known as tumor necrosis factor alpha induced protein 3 (TNFAIP3) is a key negative regulator of inflammation. But whether A20 may affect cardiac inflammation during acute viral myocarditis remains to be elucidated. The aim of this study was to investigate the potential protective effect of A20 on CVB3-induced myocarditis. Mice were intraperitoneally inoculated with CVB3 to establish acute viral myocarditis model. We found that the expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and monocyte chemotactic protein-1 (MCP-1) were markedly and persistently increased during the progression of CVB3-induced myocarditis, and positively correlated with the disease severity. Notably, intravenous injection in vivo with adenovirus expressed A20 (Ad-A20) remarkably reduced CVB3-induced pro-inflammatory cytokines production and alleviated the severity of myocarditis. Further, we observed that nuclear factor-kappaB (NF-κB) signaling which mediates inflammatory response was significantly inhibited in CVB3-infected mice with Ad-A20 treatment. Finally, we revealed that A20 was required to inhibit CVB3-induced NF-κB signaling by restricting TNF receptor associated factor 6 (TRAF6) ubiquitylation. This study demonstrates the protective role of A20 against CVB3-induced myocarditis, which may provide a new therapeutic strategy for the treatment of viral myocarditis.
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DOI：
10.1073/pnas.1006478107
发表时间：
2010-09-28
影响因子：
11.1
作者：
Garmaroudi, Farshid S.;Marchant, David;McManus, Bruce M.
通讯作者：
McManus, Bruce M.
影响因子：
4.4
作者：
Kang, Nam-In;Yoon, Ha-Yong;Park, Byung-Hyun
通讯作者：
Park, Byung-Hyun
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A
影响因子：
15.3
作者：
Grey, S T;Arvelo, M B;Hasenkamp, W;Bach, F H;Ferran, C
通讯作者：
Ferran, C
6q23 上 TNFAIP3 附近的遗传变异与系统性红斑狼疮相关。
影响因子：
30.8
作者：
Graham, Robert R.;Cotsapas, Chris;Davies, Leela;Hackett, Rachel;Lessard, Christopher J.;Leon, Joanlise M.;Burtt, Noel P.;Guiducci, Candace;Parkin, Melissa;Gates, Casey;Plenge, Robert M.;Behrens, Timothy W.;Wither, Joan E.;Rioux, John D.;Fortin, Paul R.;Graham, Deborah Cunninghame;Wong, Andrew K.;Vyse, Timothy J.;Daly, Mark J.;Altshuler, David;Moser, Kathy L.;Gaffney, Patrick M.
通讯作者：
Gaffney, Patrick M.