Osteopontin affects the persistence of β-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms
Osteopontin affects the persistence of β-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms
复制标题
DOI：
10.1093/intimm/dxh044
复制
发表时间：
2004-03-01
影响因子：
4.4
通讯作者：
Uede, T
中科院分区：
文献类型：
--
作者：
Morimoto, J;Inobe, M;Uede, T
骨桥蛋白（OPN）在多种免疫反应和炎症性疾病中起着关键作用。骨桥蛋白在各种肉芽肿性疾病中表达，然而，骨桥蛋白在这些疾病中的细胞和分子作用尚不清楚。我们分析了骨桥蛋白在β-葡聚糖诱导的肝肉芽肿模型中的作用。首先，我们发现OPN缺乏或OPN过表达均不影响第7天肝肉芽肿的数量和大小，表明OPN不参与早期肝肉芽肿的形成。重要的是，OPN不影响肝组织损伤，如在早期阶段通过丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平定义的。第二，OPN缺乏导致早期IL-12和IFN-γ产生减少。第三，在晚期，OPN缺乏导致肝肉芽肿的数量和大小减少，肝组织损伤减少。这是由于巨噬细胞、CD 4 T细胞和树突状细胞等细胞募集到肝脏中的减少，以及肝脏中肿瘤坏死因子（TNF）-α产生的减少。相反，OPN的过度表达导致肉芽肿形成的持续性。这些数据表明OPN影响肝肉芽肿形成的持续性。我们的研究结果表明，OPN在早期阶段上调肉芽肿内IL-12和IFN-γ的产生，并且OPN在决定肝组织损伤严重程度的晚期阶段的细胞募集和TNF-α产生的调节中具有额外的作用。
Osteopontin (OPN) plays a pivotal role in various immune responses and inflammatory diseases. OPN is expressed in various granulomatous diseases; however, the cellular and molecular role of OPN in these diseases is not well known. We analyzed the role of OPN in a beta-glucan-induced hepatic granuloma model. First, we found that neither OPN deficiency nor overexpression of OPN affected the number and the size of hepatic granulomas at day 7, indicating that OPN is not involved in the formation of hepatic granulomas at the early stages. Importantly, OPN did not influence the liver tissue damage as defined by alanine aminotransferase and aspartate aminotransferase levels at early stages. Second, OPN deficiency resulted in the reduction of IL-12 and IFN-gamma production at early stages. Third, at late stages, OPN deficiency resulted in a decrease in the number and size of hepatic granulomas, and a reduction of liver tissue injury. This was due to the reduction of the cellular recruitment including macrophages, CD4 T cells and dendritic cells into the liver, and the reduction of tumor necrosis factor (TNF)-alpha production in the liver. In contrast, overexpression of OPN resulted in the persistence of granuloma formation. These data suggest that OPN affects the persistence of hepatic granuloma formation. Our results indicate that OPN up-regulates the production of IL-12 and IFN-gamma within the granulomas at early stages, and OPN has an additional role in the regulation of cellular recruitment and TNF-alpha production at late stages that determine the severity of liver tissue injury.