Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice
Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice
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DOI：
10.1002/art.11231
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发表时间：
2003-09-01
影响因子：
--
通讯作者：
Fujita, S
中科院分区：
文献类型：
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作者：
Hasegawa, H;Kohno, M;Fujita, S
Objective.检测趋化因子拮抗剂是否抑制MRL/lpr小鼠狼疮性肾炎的发生和发展。将NH 2端截短的单核细胞趋化蛋白1（MCP-1）/CCL 2或胸腺和活化调节趋化因子（TARC）/CCL 17类似物插入pCXN 2表达载体中，并转染从MRL/gld小鼠建立的非转移性成纤维细胞系MRL/N-1。将MCP-1拮抗剂或TARC拮抗剂转染的MRL/N-1细胞皮下注射到7周龄（狼疮肾炎发作前）和12周龄（疾病早期）的MRL/lpr小鼠中。8周后，与对照组小鼠相比，MCP-1拮抗剂小鼠巨噬细胞和T细胞浸润、肾小球细胞过多、肾小球硬化、新月体形成和血管炎明显减少。这似乎是由于肾脏中干扰素-γ和白细胞介素-2的产生减少。而TARC拮抗剂组小鼠的肾损害与对照组相比无显著性差异。我们建立了一个新的系统，使用MRL/N-1细胞，允许长期观察趋化因子拮抗剂对MRL/lpr小鼠狼疮性肾炎的影响。我们还发现MCP-1拮抗剂可改善狼疮性肾炎和肾血管炎的发生和发展，这可能为治疗该病提供了一种新的方法。
Objective. To examine whether chemokine antagonists inhibit the initiation and progression of lupus nephritis in MRL/lpr mice.Methods. NH2-terminal-truncated monocyte chemoattractant protein 1 (MCP-1)/CCL2 or thymus and activation-regulated chemokine (TARC)/CCL17 analogs were inserted into the pCXN2 expression vector and transfected into a nonmetastatic fibroblastoid cell line, MRL/N-1, established from an MRL/gld mouse.Results. MCP-1 antagonist- or TARC antagonist-transfected MRL/N-1 cells were injected subcutaneously into MRL/lpr mice ages 7 weeks (before the onset of lupus nephritis) and 12 weeks (at the early stage of the disease). After 8 weeks, mice bearing the MCP-1 antagonist showed markedly diminished infiltration of macrophages and T cells, glomerular hypercellularity, glomerulosclerosis, crescent formation, and vasculitis compared with control mice. This seemed to be due to decreased production of interferon-gamma and interleukin-2 in the kidney. In contrast, there was no significant difference in renal damage between mice bearing TARC antagonist and control mice.Conclusion. We established a new system using MRL/N-1 cells that allows long-term observation of the effects of chemokine antagonists on lupus nephritis in MRL/lpr mice. We also showed that the MCP-1 antagonist ameliorated the initiation and progression of lupus nephritis and of renal vasculitis, which might provide a new approach to the treatment of the disease.