Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice.
Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice.
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DOI：
10.1053/j.gastro.2010.08.020
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发表时间：
2011-02
期刊：
影响因子：
29.4
通讯作者：
Szabo G
中科院分区：
文献类型：
--
作者：
Petrasek J;Dolganiuc A;Csak T;Kurt-Jones EA;Szabo G
肝脏炎症和损伤是由toll样受体（TLR）调控的先天免疫反应介导的。TLR9的激活通过干扰素调节因子(IRF)-7诱导I型干扰素（ifn）的产生。我们研究了I型ifn在小鼠tlr9相关肝损伤中的作用。通过给药TLR9或TLR2配体诱导野生型（WT）、irf7缺陷和IFN-α/s受体-1 （IFNAR1）缺陷小鼠肝损伤。在培养的肝细胞和肝单核细胞中验证了小鼠的发现，并使用重组i型IFN和白细胞介素-1受体拮抗剂（IL-1ra）进行了体内实验。在tlr9相关的WT小鼠肝损伤过程中，I型ifn表达上调。IRF7-和ifnar1缺陷小鼠，分别具有I型IFN产生或信号传导中断，具有更大程度的肝损伤和炎症，减少树突状细胞的募集，并增加肝单核细胞（LMNC）产生TNF-α。这些结果表明I型ifn在肝脏中具有抗炎活性。IL-1ra由LMNC和肝细胞产生，是ifn调控的促炎细胞因子IL-1β拮抗剂；与WT小鼠相比，IRF7-和ifnar1缺陷小鼠IL-1ra水平降低。IL-1ra保护培养的肝细胞免受il -1β介导的对TNF-α细胞毒性的致敏。体内暴露于可诱导IL-1ra的I型IFN或给予IL-1ra可减轻tlr9相关的肝损伤；因此，i型ifn的保护作用似乎是通过ifn依赖性诱导IL-1ra介导的。I型ifn具有内源性IL-1ra介导的抗炎作用，可调节tlr9诱导的肝损伤程度。因此，需要I型干扰素信号来保护免受免疫介导的肝损伤。
Liver inflammation and injury are mediated by the innate immune response, which is regulated by Toll-like receptors (TLR). Activation of TLR9 induces Type I interferons (IFNs) via the interferon regulatory factor (IRF)-7. We investigated the roles of Type I IFNs in TLR9-associated liver injury in mice. Liver injury was induced in wild-type (WT), IRF7-deficient, and IFN-α/s receptor-1 (IFNAR1)-deficient mice by administration of ligands for TLR9 or TLR2. Findings from mice were verified in cultured hepatocytes and liver mononuclear cells, and in vivo experiments using recombinant Type-I IFN and interleukin-1 receptor antagonist (IL-1ra). Type I IFNs were upregulated during TLR9-associated liver injury in WT mice. IRF7- and IFNAR1-deficient mice, which have disruptions in Type I IFN production or signaling, respectively, had greater amounts of liver damage and inflammation, decreased recruitment of dendritic cells, and increased production of TNF-α by liver mononuclear cells (LMNC). These findings indicate that Type I IFNs have anti-inflammatory activities in liver. The IL-1ra, which is produced by LMNC and hepatocytes, is an IFN-regulated antagonist of the pro-inflammatory cytokine IL-1β; IRF7- and IFNAR1-deficient mice had decreased levels of IL-1ra, compared with WT mice. IL-1ra protected cultured hepatocytes from IL-1β-mediated sensitization to cytotoxicity from TNF-α. In vivo exposure to Type I IFN, which induced IL-1ra, or administration of IL-1ra reduced TLR9-associated liver injury; the protective effect of Type-I IFNs therefore appears to be mediated by IFN-dependent induction of IL-1ra. Type I IFNs have anti-inflammatory effects mediated by endogenous IL-1ra which regulates the extent of TLR9-induced liver damage. Type I interferon signaling is therefore required for protection from immune-mediated liver injury.
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DOI：
10.1002/hep.22470
发表时间：
2008-10
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hritz I;Mandrekar P;Velayudham A;Catalano D;Dolganiuc A;Kodys K;Kurt-Jones E;Szabo G
通讯作者：
Szabo G
影响因子：
24.5
作者：
Mencin A;Kluwe J;Schwabe RF
通讯作者：
Schwabe RF
影响因子：
4.4
作者：
Itakura, M;Tokuda, A;Matsushima, K
通讯作者：
Matsushima, K
影响因子：
13.5
作者：
Moritoki, Yuki;Lian, Zhe-Xiong;Gershwin, M. Eric
通讯作者：
Gershwin, M. Eric
影响因子：
64.8
作者：
Honda, K;Ohba, Y;Taniguchi, T
通讯作者：
Taniguchi, T