Cell Biology – Immunology – Pathology
Kidney International (1999) 55, 1319–1326; doi:10.1046/j.1523-1755.1999.00354.x
Interleukin-4 ameliorates crescentic glomerulonephritis in Wistar Kyoto rats
H Terence Cook, Sharon J Singh, David E Wembridge, Jennifer Smith, Frederick W K Tam and Charles D Pusey
Departments of Histopathology and Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, England, United Kingdom
Correspondence: Dr H. Terence Cook, Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, England, United Kingdom. E-mail: t.cook@rpms.ac.uk
Received 31 July 1998; Revised 2 November 1998; Accepted 3 November 1998.
Abstract
Interleukin-4 ameliorates crescentic glomerulonephritis in Wistar Kyoto rats.
Background
Activated macrophages play a central role in crescentic glomerulonephritis. Interleukin-4 (IL-4) down-regulates many macrophage proinflammatory activities. We therefore studied the effect of IL-4 on glomerular injury in a model of crescentic glomerulonephritis in the Wistar Kyoto rat.
Methods
Glomerulonephritis was induced by i.v. administration of rabbit antirat glomerular basement membrane antiserum (nephrotoxic serum, NTS). In experiment 1, IL-4 was given from two hours before NTS until day 6. In experiment 2, rats were treated from day 0 to 7 and were then monitored until killed on day 28. In experiment 3, IL-4 was given from day 4 to 7.
Results
Continuous IL-4 treatment (experiment 1) significantly (P = 0.001) reduced proteinuria (3 
1 mg per 24 hr vs. 56 7), fibrinoid necrosis (0.06 0.04 quadrants/glomulus vs. 1.2 0.1), macrophage infiltration (6.7 2.6 cells/glom vs. 33 2.5), CD8+ cells (1.5 0.6 cells/glom vs. 6.2 1.1), inducible nitric oxide synthase positive cells (0.04 0.04 cells/glom vs. 3.7 0.6), proliferating cell nuclear antigen positive cells (3.2 1 cells/glom vs. 15 2.3), and glomerular intercellular adhesion molecule-1 expression. Follow-up after seven days of treatment (experiment 2) showed that at four weeks, creatinine clearance was higher in treated rats (1.1 0.1 ml/min vs. 0.4 01, P = 0.011), and both glomerular scarring (P = 0.006) and tubular atrophy (P = 0.006) were less. Delayed treatment (experiment 3) reduced proteinuria (41 5 mg per 24 hr vs. 97 9, P = 0.004) and fibrinoid necrosis (0.39 0.05 quadrants/glom vs. 1.6 0.1, P = 0.004). There was no difference in macrophage infiltration, but inducible nitric oxide synthase positive cells were reduced (0.6 0.1 cells/glom vs. 1.8 0.4, P = 0.01) as were ED3+ cells (0.18 0.06 cells/glom vs. 1.86 0.21, P = 0.004).
Conclusion
In this model of crescentic glomerulonephritis, early IL-4 treatment abolished proteinuria and markedly reduced glomerular inflammation. If treatment was stopped after seven days, there was continuing benefit on glomerular and tubulointerstitial scarring and creatinine clearance at four weeks. If treatment was delayed until inflammation was established, there was still a reduction of injury, but without an alteration of macrophage numbers, suggesting that IL-4 may be acting, in part, to reduce macrophage activation.
Keywords:
macrophage activation, inflammation, glomerular injury, proteinuria, tubulointerstitial scarring
