Endogenous interleukin-10 regulates Th1 responses that induce crescentic glomerulonephritis

Abstract

Endogenous interleukin-10 regulates Th1 responses that induce crescentic glomerulonephritis.BackgroundInterleukin (IL)-10 plays a pivotal role in regulating the Th1/Th2 predominance of immune responses. Exogenously administered IL-10 suppresses nephritogenic Th1 responses, inhibits macrophage function, and attenuates crescentic glomerulonephritis (GN). To determine the role of endogenous IL-10, the development of the nephritogenic immune response and crescentic GN was compared in IL-10–deficient (IL-10-/-) and normal (IL-10+/+) C57BL/6 mice.MethodsGN was initiated in sensitized mice by the intravenous administration of sheep antimouse glomerular basement membrane globulin. Renal injury was evaluated 21 days later.ResultsFollowing the administration of anti-glomerular basement membrane globulin, normal (IL-10+/+) C57BL/6 mice developed proliferative GN with occasional crescents, glomerular CD4+ T-cell and macrophage accumulation, and fibrin deposition. Using an identical induction protocol, IL-10-/-mice developed more severe GN. Crescent formation (IL-10-/-, 23 ± 2% of glomeruli; IL-10+/+, 5 ± 2%), glomerular CD4+ T cells [IL-10-/-, 1.0 ± 0.2 cells per glomerular cross-section (c/gcs); IL-10 +/+, 0.3 ± 0.05 c/gcs], glomerular macrophages (IL-10-/-, 4.8 ± 0.3 c/gcs; IL-10 +/+, 1.7 ± 0.2 c/gcs), fibrin deposition [fibrin score (range 0 to 3+); IL-10-/-, 1.10 ± 0.04; IL-10+/+, 0.6 ± 0.07], and serum creatinine (IL-10-/-, 30 ± 2 μmol/L; IL-10 +/+, 23 ± 1 μmol/L) were all significantly increased in IL-10-/- mice (P < 0.05). Circulating antibody (IL-10-/-, 1.05 ± 0.16 OD units; IL-10+/+, 0.63 ± 0.08 OD units) and cutaneous delayed-type hypersensitivity (skin swelling; IL-10-/-, 0.21 ± 0.03 mm; IL-10+/+, 0.12 ± 0.02 mm) to the nephritogenic antigen (sheep globulin) were also increased (both P < 0.05). Interferon-γ production by cultured splenocytes was increased (IL-10-/- 7.9 ± 2.5 ng/4 × 106 cells, IL-10+/+ 0.28 ± 0.09 ng/4 × 106 cells, P < 0.05), but IL-4 production was unchanged.ConclusionsEndogenous IL-10 counter-regulates nephritogenic Th1 responses and attenuates crescentic GN. Endogenous interleukin-10 regulates Th1 responses that induce crescentic glomerulonephritis. Interleukin (IL)-10 plays a pivotal role in regulating the Th1/Th2 predominance of immune responses. Exogenously administered IL-10 suppresses nephritogenic Th1 responses, inhibits macrophage function, and attenuates crescentic glomerulonephritis (GN). To determine the role of endogenous IL-10, the development of the nephritogenic immune response and crescentic GN was compared in IL-10–deficient (IL-10-/-) and normal (IL-10+/+) C57BL/6 mice. GN was initiated in sensitized mice by the intravenous administration of sheep antimouse glomerular basement membrane globulin. Renal injury was evaluated 21 days later. Following the administration of anti-glomerular basement membrane globulin, normal (IL-10+/+) C57BL/6 mice developed proliferative GN with occasional crescents, glomerular CD4+ T-cell and macrophage accumulation, and fibrin deposition. Using an identical induction protocol, IL-10-/-mice developed more severe GN. Crescent formation (IL-10-/-, 23 ± 2% of glomeruli; IL-10+/+, 5 ± 2%), glomerular CD4+ T cells [IL-10-/-, 1.0 ± 0.2 cells per glomerular cross-section (c/gcs); IL-10 +/+, 0.3 ± 0.05 c/gcs], glomerular macrophages (IL-10-/-, 4.8 ± 0.3 c/gcs; IL-10 +/+, 1.7 ± 0.2 c/gcs), fibrin deposition [fibrin score (range 0 to 3+); IL-10-/-, 1.10 ± 0.04; IL-10+/+, 0.6 ± 0.07], and serum creatinine (IL-10-/-, 30 ± 2 μmol/L; IL-10 +/+, 23 ± 1 μmol/L) were all significantly increased in IL-10-/- mice (P < 0.05). Circulating antibody (IL-10-/-, 1.05 ± 0.16 OD units; IL-10+/+, 0.63 ± 0.08 OD units) and cutaneous delayed-type hypersensitivity (skin swelling; IL-10-/-, 0.21 ± 0.03 mm; IL-10+/+, 0.12 ± 0.02 mm) to the nephritogenic antigen (sheep globulin) were also increased (both P < 0.05). Interferon-γ production by cultured splenocytes was increased (IL-10-/- 7.9 ± 2.5 ng/4 × 106 cells, IL-10+/+ 0.28 ± 0.09 ng/4 × 106 cells, P < 0.05), but IL-4 production was unchanged. Endogenous IL-10 counter-regulates nephritogenic Th1 responses and attenuates crescentic GN.