Interleukin-11 attenuates nephrotoxic nephritis in Wistar Kyoto rats.
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.
Lai
Ping-Chin
PC
Renal Section, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Cook
H Terence
HT
Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Smith
Jennifer
J
Renal Section, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Keith
James C
JC
Department of Immunology and Hemostasis, Discovery Research, Wyeth/Genetics Institute Inc., Andover, Massachusetts.
Pusey
Charles D
CD
Renal Section, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Tam
Frederick W K
FWK
Renal Section, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000473:pathology* / Q000503:physiopathology*; D001483:Base Sequence / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007274:Injections, Intraperitoneal; D017370:Interleukin-11 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009336:Necrosis; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011921:Rats, Inbred WKY; D011971:Receptors, Immunologic / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012689:Sequence Homology, Nucleic Acid; D063267:Sialic Acid Binding Ig-like Lectin 1
D017370:Interleukin-11; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D011994:Recombinant Proteins; C571166:SIGLEC1 protein, human; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse