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.
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.
Authors: Christian Kurts; Felix Heymann; Veronika Lukacs-Kornek; Peter Boor; Jürgen Floege Journal: Semin Immunopathol Date: 2007-10-23 Impact factor: 9.623
Authors: Shaun A Summers; Oliver M Steinmetz; Joshua D Ooi; Poh-yi Gan; Kim M O'Sullivan; Kumar Visvanathan; Shizuo Akira; A Richard Kitching; Stephen R Holdsworth Journal: Am J Pathol Date: 2010-09-16 Impact factor: 4.307
Authors: Jacques Behmoaras; Gurjeet Bhangal; Jennifer Smith; Kylie McDonald; Brenda Mutch; Ping Chin Lai; Jan Domin; Laurence Game; Alan Salama; Brian M Foxwell; Charles D Pusey; H Terence Cook; Timothy J Aitman Journal: Nat Genet Date: 2008-05 Impact factor: 38.330