IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease.
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| Abstract |
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.
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| Authors | Wei Mu, Xiaosen Ouyang, Anupam Agarwal, Li Zhang, David A Long, Pedro E Cruz, Carlos A Roncal, Olena Y Glushakova, Vince A Chiodo, Mark A Atkinson, William W Hauswirth, Terry R Flotte, Bernardo Rodriguez-Iturbe, Richard J Johnson |
| Journal | Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 16 Issue 12 Pg. 3651-60 (Dec 2005) ISSN: 1046-6673 [Print] United States |
| PMID | 16251240 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Chemical References |
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