Suppression of experimental crescentic glomerulonephritis by the interleukin-1 receptor antagonist.
The role of interleukin-1 (IL-1) in the pathogenesis of experimental crescentic glomerulonephritis was investigated. Administration of the interleukin-1 receptor antagonist (IL-1ra) was used to block the action of IL-1 during disease development. Two groups of six rats were primed with rabbit IgG, followed five days later by injection of rabbit anti-GBM serum (day 0). Animals were treated with a constant infusion of recombinant human IL-1ra (plasma level approximately 100 to 200 ng/ml) or saline (untreated) from day -1 until being killed on day 14. Untreated animals exhibited severe proteinuria and development renal dysfunction shown by increased serum urea and serum creatinine and reduced creatinine clearance. In contrast, IL-1ra treated animals had significantly reduced proteinuria (IL-1ra vs. untreated, P < 0.05) and maintained normal renal function (IL-1ra vs. untreated, P < 0.05). Histologically, IL-1ra treatment markedly reduced glomerular hypercellularity, glomerular necrosis and crescent formation and almost completely abrogated tubular atrophy and fibrosis. IL-1ra treatment suppressed glomerular macrophage accumulation by 57% (P < 0.01), while macrophage accumulation in the interstitium was completely abrogated and immune activation of the interstitial T cell infiltrate was prevented. This study demonstrates that IL-1 plays a key role in the pathogenesis of anti-GBM glomerulonephritis, and blocking its effects may provide a novel therapeutic approach to the treatment of human progressive glomerulonephritis.
Lan
H Y
HY
Department of Nephrology, Monash Medical Centre, Melbourne, Australia.
Nikolic-Paterson
D J
DJ
Zarama
M
M
Vannice
J L
JL
Atkins
R C
RC
D000818:Animals; D001485:Basement Membrane / Q000276:immunology; D003176:Complement C3 / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007074:Immunoglobulin G / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000494:pharmacology*
D003176:Complement C3; C507763:IL1RN protein, human; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins