Endogenous interleukin-10 regulates Th1 responses that induce crescentic glomerulonephritis.
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.
Kitching
A R
AR
Center for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia. richard.kitching@med.monash.edu.au
Tipping
P G
PG
Timoshanko
J R
JR
Holdsworth
S R
SR
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001323:Autoantibodies; D003176:Complement C3 / Q000032:analysis / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D005337:Fibrin / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007136:Immunoglobulins / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000276:immunology; D012756:Sheep; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*
D000906:Antibodies; D001323:Autoantibodies; D003176:Complement C3; D016207:Cytokines; D007136:Immunoglobulins; C051951:antiglomerular basement membrane antibody; D016753:Interleukin-10; D007371:Interferon-gamma; D005337:Fibrin