Interleukin-12 from intrinsic cells is an effector of renal injury in crescentic glomerulonephritis.
Interleukin-12 (IL-12) directs the cognate nephritogenic T helper type 1 responses that initiate renal injury in murine crescentic glomerulonephritis (GN). The recent demonstration of IL-12 production by intrinsic renal cells, including mesangial and proximal tubular cells, raises the possibility that IL-12 from nonimmune cells may contribute to inflammatory renal injury. To address this possibility, the development of sheep anti-mouse glomerular basement membrane globulin-induced crescentic GN was studied in C57BL/6 wild-type (WT), IL-12-deficient (IL-12 -/-), and IL-12 "chimeric" mice. IL-12 chimeric mice were produced by transplantation of WT bone marrow into IL-12 -/- mice to restore IL-12 production by immune cells, while leaving them deficient in renal IL-12 production. WT and "sham" chimeric mice (normal bone marrow transplanted into WT mice) developed crescentic GN with glomerular T-cell and macrophage recruitment and impaired renal function (elevated proteinuria and serum creatinine) 10 d after initiation of GN. IL-12 -/- mice showed significant protection from GN. Chimeric IL-12 mice showed significant attenuation of crescent formation, glomerular T-cell and macrophage accumulation, and renal impairment, compared with WT and sham chimeric mice, but were not protected to the same extent as IL-12 -/- mice. IL-12 chimeric mice showed no attenuation of their systemic cognate immune response to the nephritogenic antigen (sheep globulin), indicated by antigen-specific circulating antibody and cutaneous delayed-type hypersensitivity. These studies indicate that IL-12 produced by non-bone marrow derived intrinsic renal cells contributes to immune renal injury. They provide the first in vivo demonstration of a proinflammatory role for an intrinsic renal cell-derived cytokine in renal inflammation.
Timoshanko
Jennifer R
JR
From the Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia.
Kitching
A Richard
AR
From the Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia.
Holdsworth
Stephen R
SR
From the Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia.
Tipping
Peter G
PG
From the Center for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Center, Clayton, Victoria, Australia.
D000818:Animals; D016026:Bone Marrow Transplantation; D002678:Chimera; D005916:Globulins / Q000276:immunology; D005921:Glomerulonephritis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D006968:Hypersensitivity, Delayed; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012756:Sheep
D005916:Globulins; D018664:Interleukin-12