Interleukin-11 attenuates nephrotoxic nephritis in Wistar Kyoto rats

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 400μg 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 (EDI-positive cells, 24.4 ± 1.8 versus 39.3 ± 1.9 cells/gcs) cells/-cs), 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 synthasepositive 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 transcriptasepolymerase chain reaction showed that the mRNA ratio of IL-1β/β-actin in the treated rats was reduced compared with controls. By the use of probes designed from mouse IL-11 receptor a-chain sequence, it was also shown that rat mesan gial cells and macrophages expressed IL-11 receptor a-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.