首页> 外文期刊>Clinical immunology: The official journal of the Clinical Immunology Society >Toll-like receptor 4-induced cytokine production circumvents protection conferred by TGF-beta in coxsackievirus-mediated autoimmune myocarditis.
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Toll-like receptor 4-induced cytokine production circumvents protection conferred by TGF-beta in coxsackievirus-mediated autoimmune myocarditis.

机译:Toll样受体4诱导的细胞因子产生绕过了由TGF-β介导的柯萨奇病毒介导的自身免疫性心肌炎的保护作用。

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摘要

Coxsackie B virus (CBV) infections are a leading cause of autoimmune myocarditis associated with inflammatory heart disease and sudden death in young adults. Previously, we demonstrated that transgenic expression of the immunosuppressive cytokine, transforming growth factor-beta (TGF-beta), specifically in the pancreas protected otherwise susceptible mice from CBV-mediated autoimmune myocarditis. Herein, we demonstrate that macrophages from these transgenic mice fail to upregulate the costimulatory molecule CD40 following infection, suggesting that pancreatic TGF-beta protects by limiting antigen stimulation. We further demonstrate that co-administration of LPS from Salmonella minnesota, a Toll-like receptor (TLR)-4 ligand, with CBV infection overcomes protection whereas the TLR-2 agonist, LPS from Porphyromonas gingivalis, does not. Furthermore, LPS-mediated disease induction correlates with increased levels of pro-inflammatory cytokines. Interestingly, the action of LPS (TLR-4) did not alter antibodyisotype switching, increase viral replication or modulate CD40 expression. Instead, LPS breaks protection through an alternative mechanism specific to TLR-4 signaling.
机译:柯萨奇B病毒(CBV)感染是自身免疫性心肌炎的主要原因,与年轻人发炎的心脏病和猝死有关。以前,我们证明了免疫抑制性细胞因子的转基因表达,特别是在胰腺中转化生长因子-β(TGF-β)的表达,可以保护其他易感小鼠免受CBV介导的自身免疫性心肌炎的侵害。在本文中,我们证明了来自这些转基因小鼠的巨噬细胞在感染后未能上调共刺激分子CD40,这表明胰腺TGF-β通过限制抗原刺激来提供保护。我们进一步证明,与明尼苏达州沙门氏菌(Toll样受体(TLR)-4配体)的LPS与CBV感染并用可以克服保护作用,而TLR-2激动剂(来自齿龈卟啉单胞菌)的LPS则不能。此外,LPS介导的疾病诱导与促炎细胞因子水平升高相关。有趣的是,LPS(TLR-4)的作用不会改变抗体同种型转换,不会增加病毒复制或调节CD40表达。相反,LPS通过特定于TLR-4信令的替代机制破坏了保护。

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