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J Am Soc Nephrol 12:2310-2320, 2001
© 2001 American Society of Nephrology

Interleukin-11 Attenuates Nephrotoxic Nephritis in Wistar Kyoto Rats

PING-CHIN LAI*, H. TERENCE COOK{dagger}, JENNIFER SMITH*, JAMES C. KEITH, JR.{ddagger}, CHARLES D. PUSEY* and FREDERICK W. K. TAM*

* Renal Section, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
{dagger} Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
{ddagger} Department of Immunology and Hemostasis, Discovery Research, Wyeth/Genetics Institute Inc., Andover, Massachusetts.

Correspondence to Dr. Frederick W. K. Tam, Renal Section, Department of Medicine, Imperial College, School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20 8383 3936; Fax: 44-20 8383 2062; E-mail: f.tam{at}ic.ac.uk

Abstract. 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 µg) was given 2 h before nephrotoxic serum, then once daily until day 6. In experiment 2, a lower dose of IL-11 (800 µg/d) was used. Rats were treated either with IL-11 400 µg twice daily intraperitoneally or with 800 µg 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-1ß/ß-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.




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