Endogenous interleukin-10 regulates Th1 responses that induce crescentic glomerulonephritis

Kidney Int. 2000 Feb;57(2):518-25. doi: 10.1046/j.1523-1755.2000.00872.x.

Abstract

Background: 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.

Methods: GN was initiated in sensitized mice by the intravenous administration of sheep antimouse glomerular basement membrane globulin. Renal injury was evaluated 21 days later.

Results: 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 micromol/L; IL-10 +/+, 23 +/- 1 micromol/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-gamma production by cultured splenocytes was increased (IL-10-/- 7.9 +/- 2. 5 ng/4 x 106 cells, IL-10+/+ 0.28 +/- 0.09 ng/4 x 106 cells, P < 0. 05), but IL-4 production was unchanged.

Conclusions: Endogenous IL-10 counter-regulates nephritogenic Th1 responses and attenuates crescentic GN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • Autoantibodies
  • Complement C3 / analysis
  • Complement C3 / immunology
  • Cytokines / immunology
  • Female
  • Fibrin / immunology
  • Gene Expression / immunology
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology
  • Hypersensitivity, Delayed / immunology*
  • Immunoglobulins / immunology
  • Immunoglobulins / pharmacology
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / analysis
  • Interleukin-10 / genetics*
  • Interleukin-10 / immunology
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / pathology
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding / immunology
  • Sheep
  • Species Specificity
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism
  • Th1 Cells / immunology*

Substances

  • Antibodies
  • Autoantibodies
  • Complement C3
  • Cytokines
  • Immunoglobulins
  • antiglomerular basement membrane antibody
  • Interleukin-10
  • Interferon-gamma
  • Fibrin