Lai Ping-Chin, Cook H Terence, Smith Jennifer, Keith James C, Pusey Charles D, Tam Frederick W K
Renal Section, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
J Am Soc Nephrol. 2001 Nov;12(11):2310-2320. doi: 10.1681/ASN.V12112310.
Interleukin-11 (IL-11) is a multifuctional cytokine with anti-inflammatory activity. The effect of IL-11 was studied in an experimental model of necrotizing glomerulonephritis induced in Wistar Kyoto rats by an injection of anti-glomerular basement membrane antibody (nephrotoxic serum). Intraperitoneal injection was chosen as the route of IL-11 administration in all experiments. In experiment 1, recombinant human IL-11 (1360 microg) was given 2 h before nephrotoxic serum, then once daily until day 6. In experiment 2, a lower dose of IL-11 (800 microg/d) was used. Rats were treated either with IL-11 400 microg twice daily intraperitoneally or with 800 microg once daily intraperitoneally for 6 d. In experiment 3, the lower dose of IL-11 was given 2 h before nephrotoxic serum, then twice daily until day 2. In experiment 1, IL-11 significantly reduced proteinuria (13.2 +/- 3.3 versus 63.2 +/- 4.3 mg/24 h), fibrinoid necrosis (0.58 +/- 0.08 versus 1.52 +/- 0.06 quadrants/glomerular cross section [gcs]), macrophage infiltration (ED1-positive cells, 24.4 +/- 1.8 versus 39.3 +/- 1.9 cells/gcs), apoptosis (1.11 +/- 0.1 versus 2.39 +/- 0.2 apoptotic bodies/gcs), and proliferating cell nuclear antigen-positive cells (24.4 +/- 2.0 versus 37.3 +/- 2.3 cells/gcs). Inducible nitric oxide synthase-positive cells were significantly increased (3.1 +/- 0.3 versus 2.0 +/- 0.2 cells/gcs). In experiment 2, a lower dose of IL-11 significantly reduced proteinuria and fibrinoid necrosis. Macrophage infiltration was similar in treated and control groups, although the number of sialoadhesin-positive macrophages (ED3+) was significantly reduced in the IL-11-treated rats. In experiment 3, quantitative competitive reverse transcriptase-polymerase chain reaction showed that the mRNA ratio of IL-1 beta/beta-actin in the treated rats was reduced compared with controls. By the use of probes designed from mouse IL-11 receptor alpha-chain sequence, it was also shown that rat mesangial cells and macrophages expressed IL-11 receptor alpha-chain, demonstrating that they were capable of responding to IL-11. In this model of necrotizing glomerulonephritis, high-dose IL-11 treatment markedly reduced both proteinuria and fibrinoid necrosis. At the lower dose, there was a reduction in glomerular injury and macrophage sialoadhesin expression, but without an alteration of macrophage numbers, suggesting that IL-11 may be acting in part to reduce macrophage activation.
白细胞介素-11（IL-11）是一种具有抗炎活性的多功能细胞因子。在通过注射抗肾小球基底膜抗体（肾毒性血清）诱导的Wistar Kyoto大鼠坏死性肾小球肾炎实验模型中研究了IL-11的作用。在所有实验中均选择腹腔注射作为IL-11给药途径。在实验1中，在注射肾毒性血清前2小时给予重组人IL-11（1360微克），然后每日一次直至第6天。在实验2中，使用较低剂量的IL-11（800微克/天）。大鼠分别接受腹腔内每日两次400微克IL-11或腹腔内每日一次800微克IL-11治疗6天。在实验3中，在注射肾毒性血清前2小时给予较低剂量的IL-11，然后每日两次直至第2天。在实验1中，IL-11显著降低蛋白尿（13.2±3.3对63.2±4.3毫克/24小时）、纤维蛋白样坏死（0.58±0.08对1.52±0.06象限/肾小球横截面[gcs]）、巨噬细胞浸润（ED1阳性细胞，24.4±1.8对39.3±1.9细胞/gcs）、细胞凋亡（1.11±0.1对2.39±0.2凋亡小体/gcs）以及增殖细胞核抗原阳性细胞（24.4±2.0对37.3±2.3细胞/gcs）。诱导型一氧化氮合酶阳性细胞显著增加（3.1±0.3对2.0±0.2细胞/gcs）。在实验2中，较低剂量的IL-11显著降低蛋白尿和纤维蛋白样坏死。治疗组和对照组的巨噬细胞浸润相似，尽管在接受IL-11治疗的大鼠中唾液酸粘附素阳性巨噬细胞（ED3 +）的数量显著减少。在实验3中，定量竞争性逆转录聚合酶链反应显示，与对照组相比，治疗组大鼠中IL-1β/β-肌动蛋白的mRNA比率降低。通过使用从小鼠IL-11受体α链序列设计的探针，还表明大鼠系膜细胞和巨噬细胞表达IL-11受体α链，表明它们能够对IL-11作出反应。在这种坏死性肾小球肾炎模型中，高剂量IL-11治疗显著降低蛋白尿和纤维蛋白样坏死。在较低剂量时，肾小球损伤和巨噬细胞唾液酸粘附素表达降低，但巨噬细胞数量无改变，这表明IL-11可能部分作用是减少巨噬细胞活化。
