IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease
IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease
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DOI：
10.1681/asn.2005030297
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发表时间：
2005-12-01
影响因子：
13.6
通讯作者：
Johnson, RJ
中科院分区：
文献类型：
--
作者：
Mu, W;Ouyang, X;Johnson, RJ
IL-10 是一种多能细胞因子，在免疫和炎症反应的调节中发挥着关键作用。尽管短期给予 IL-10 对急性肾小球肾炎有好处，但尚无研究探讨 IL-10 对慢性肾病的潜在益处。通过给予重组腺相关病毒血清型 1 IL-10 (rAAV1-IL-10) 载体，可以实现大鼠血液中 IL-10 水平的长期升高。对照大鼠被给予相似剂量的rAAV1-GFP。注射后4周，通过ELISA测定血清中IL-10水平，并通过5/6肾切除术诱导慢性肾病（每组n = 6）。八周后，处死大鼠并获取肾组织用于 RNA、蛋白质和免疫组织化学分析。 rAAV1-IL-10给药后4周，rAAV1-IL-.10组中IL-10的血清水平增加了12倍（345 +/- 169 vs 28±15 pg/ml；P = 0.001），并且在整个实验过程中维持该水平。与 rAAV1-GFP 治疗的大鼠相比，rAAV1-IL-10 治疗导致蛋白尿减少（P < 0.05）、血清肌酐降低（P < 0.05）和肌酐清除率升高（P < 0.01）。通过CD4(+)、CD8(+)、单核巨噬细胞(ED-1(+))和树突状细胞(OX-62(+))细胞的数量评估，rAAV1-IL-10给药后肾间质浸润显着减弱(P < 0.05)，这与单核细胞(肾单核细胞趋化蛋白-1 mRNA和肾单核细胞趋化蛋白-1 mRNA)的肾脏表达的减少相关。 蛋白）和 T 细胞（RANTES mRNA）趋化因子。 rAAV1-IL-10 给药降低了肾脏中 IFN-γ 和 IL-2 的 mRNA 水平。炎症细胞的减少与肾小球硬化和间质纤维化的显着减少相关。结论是，在慢性肾病模型中，IL-10 可阻断炎症并改善肾功能。还证明了在肾病模型中使用 AAV 血清型 1 载体系统长期过度表达基因的可行性。
IL-10 is a pluripotent cytokine that plays a pivotal role in the regulation of immune and inflammatory responses. Whereas short-term administration of IL-10 has shown benefit in acute glomerulonephritis, no studies have addressed the potential benefits of IL-10 in chronic renal disease. Chronically elevated blood levels of IL-10 in rats were achieved by administration of a recombinant adeno-associated virus serotype 1 IL-10 (rAAV1-IL-10) vector. Control rats were given a similar dose of rAAV1-GFP. Four weeks after injection, IL-10 levels in serum were measured by ELISA, and chronic renal disease was induced by a 5/6 nephrectomy (n = 6 in each group). Eight weeks later, rats were killed and renal tissue was obtained for RNA, protein, and immunohistochemical analysis. Serum levels of IL-10 were 12-fold greater in the rAAV1-IL-.10 group by 4 wk after rAAV1-IL-10 administration (345 +/- 169 versus 28 15 pg/ml; P = 0.001), and levels were maintained throughout the experiment. rAAV1-IL-10 treatment resulted in less proteinuria (P < 0.05), lower serum creatinine (P < 0.05), and higher creatinine clearances (P < 0.01) compared with rAAV1-GFP-treated rats. Renal interstitial infiltration was significantly attenuated by rAAV1-IL-10 administration as assessed by numbers of CD4(+), CD8(+), monocyte-macrophages (ED-1(+)) and dendritic (OX-62(+)) cells (P < 0.05), and this correlated with reductions in the renal expression of monocyte (renal monocyte chemoattractant protein-1 mRNA and protein) and T cell (RANTES mRNA) chemokines. rAAV1-IL-10 administration decreased mRNA levels of IFN-gamma and IL-2 in the kidney. The reduction in inflammatory cells was associated with a significant reduction in glomerulosclerosis and interstitial fibrosis. It is concluded that IL-10 blocks inflammation and improves renal function in this model of chronic renal disease. The feasibility of long-term overexpression of a gene using the AAV serotype 1 vector system in a model of renal disease is also demonstrated.