IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice
IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice
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DOI：
10.1002/art.22172
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发表时间：
2006-11-01
影响因子：
--
通讯作者：
Yasukawa, Masaki
中科院分区：
文献类型：
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作者：
Muraoka, Masatake;Hasegawa, Hitoshi;Yasukawa, Masaki
Objective. IK细胞因子已被分离为抑制干扰素-γ（IFN γ）诱导的II类主要组织相容性复合体（MHC）抗原表达的因子。据报道，II类MHC抗原的异常表达在自身免疫性疾病的靶器官中被识别，并且与疾病活动相关。在这项研究中，我们研究了IK细胞因子是否可以改善MRL/lpr小鼠狼疮性肾炎的进展。制备截短的IK类似物，转染非转移性成纤维细胞系，然后皮下注射8周龄（狼疮肾炎发病前）和12周龄（狼疮肾炎早期）的MRL/lpr小鼠。IK细胞因子，当它从甲硫氨酸在位置316处翻译时，充当分泌蛋白。这种截短的IK细胞因子（tIK）通过降低11类MHC转录激活因子的表达而降低IFN γ诱导的各种细胞中11类MHC的表达。与对照小鼠相比，用tIK治疗MRL/lpr小鼠显著降低了肾损伤。在tIK处理的小鼠的肾脏中发现巨噬细胞和T细胞浸润的显著减少，导致IFN γ和白细胞介素-2的产生减少。用tIK治疗的小鼠也显示出抗DNA抗体和循环免疫复合物的显著减少。在B细胞和单核细胞以及肾脏中观察到II类MHC表达的特异性降低。我们制备了一种有效的IK类似物，并证明了其改善狼疮性肾炎进展的能力。因此，这种药物可能为狼疮性肾炎提供一种新的治疗方法。
Objective. IK cytokine has been isolated as a factor that inhibits interferon-y (IFNy)-induced expression of class II major histocompatibility complex (MHC) antigens. Aberrant expression of class II MHC antigens has reportedly been recognized in the target organs of autoimmune diseases and been associated with disease activity. In this study, we investigated whether IK cytokine can ameliorate the progression of lupus nephritis in MRL/lpr mice.Methods. A truncated IK analog was prepared and transfected into a nonmetastatic fibroblastoid cell line, and then injected subcutaneously into MRL/lpr mice at ages 8 weeks (before the onset of lupus nephritis) and 12 weeks (at the early stage of the disease).Results. An IK cytokine, when it was translated from methionine at position 316, acted as a secretory protein. This truncated IK cytokine (tIK) reduced IFN gamma-induced class 11 MHC expression in various cells through decreased expression of class 11 MHC transcription activator. Treatment of MRL/lpr mice with tIK significantly reduced renal damage as compared with control mice. A significant decrease in macrophage and T cell infiltration was found in the kidneys of tIK-treated mice, resulting in decreased production of IFNy and interleukin-2. Mice treated with tIK also showed significant reduction of anti-DNA antibodies and circulating immune complexes. A specific reduction of class II MHC expression was observed on B cells and monocytes as well as in the kidney.Conclusion. We prepared a potent IK analog and demonstrated its ability to ameliorate the progression of lupus nephritis. This agent may therefore provide a new therapeutic approach for lupus nephritis.