CC chemokine ligand 5/RANTES chemokine antagonists aggravate glomerulonephritis despite reduction of glomerular leukocyte infiltration
CC chemokine ligand 5/RANTES chemokine antagonists aggravate glomerulonephritis despite reduction of glomerular leukocyte infiltration
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DOI：
10.4049/jimmunol.170.11.5658
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发表时间：
2003-06-01
影响因子：
4.4
通讯作者：
Schlöndorff, D
中科院分区：
文献类型：
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作者：
Anders, HJ;Frink, M;Schlöndorff, D
趋化因子CC趋化因子配体(CCL)5/RANTES及其受体CCR5介导炎症过程中白细胞的浸润，并在肾小球肾炎(GN)早期上调。我们检测了两种CCL5/RANTES阻断类似物Met-RANTES和氨基-氧戊烷-RANTES对马载脂蛋白(RAF)诱导的肾小球肾炎过程的影响。注射HAF的对照组小鼠GN呈增生性，系膜免疫复合体沉积有Ig G和HAF。每日ip。注射Met-RANTES或氨基-氧戊烷-RANTES可显著减少肾小球细胞增殖和肾小球巨噬细胞浸润，这通常与RAF-GN肾小球损伤和蛋白尿减少有关。然而，令人惊讶的是，使用这两种类似物治疗的RAF-GN小鼠表现出更严重的疾病，表现为系膜溶解、毛细血管阻塞和肾病范围蛋白尿。这些发现与CCL5/RANTES类似物对巨噬细胞激活状态的增强作用有关，其特征是在体外和体内具有明显的形态特征和诱导的NO合成酶表达增加，但在体内对凋亡细胞的摄取减少。CCL5/RANTES类似物不影响HAF-GN的不道德反应、Th1/Th2平衡和体外系膜细胞增殖。我们的结论是，尽管阻止了局部的白细胞募集，趋化因子类似物可以加重某些特定的疾病模型，很可能是由于与全身免疫反应的相互作用，包括去除凋亡细胞和诱导一氧化氮合酶的表达。
The chemokine CC chemokine ligand (CCL)5/RANTES as well as its respective receptor CCR5 mediate leukocyte infiltration during inflammation and are up-regulated early during the course of glomerulonephritis (GN). We tested the effects of the two CCL5/RANTES blocking analogs, Met-RANTES and amino-oxypentane-RANTES, on the course of horse apoferritin (RAF)induced GN. HAF-injected control mice had proliferative GN with mesangial immune complex deposits of IgG and HAF. Daily i.p. injections of Met-RANTES or amino-oxypentane-RANTES markedly reduced glomerular cell proliferation and glomerular macrophage infiltration, which is usually associated with less glomerular injury and proteinuria in RAF-GN. Surprisingly, however, RAF-GN mice treated with both analogs showed worse disease with mesangiolysis, capillary obstruction, and nephrotic range albuminuria. These findings were associated with an enhancing effect of the CCL5/RANTES analogs on the macrophage activation state, characterized by a distinct morphology and increased inducible NO synthetase expression in vitro and in vivo, but a reduced uptake of apoptotic cells in vivo. The Immoral response and the Th1/Th2 balance in HAF-GN and mesangial cell proliferation in vitro were not affected by the CCL5/RANTES analogs. We conclude that, despite blocking local leukocyte recruitment, chemokine analogs can aggravate some specific disease models, most likely due to interactions with systemic immune reactions, including the removal of apoptotic cells and inducible NO synthetase expression.