Leukocyte-derived interleukin-1beta interacts with renal interleukin-1 receptor I to promote renal tumor necrosis factor and glomerular injury in murine crescentic glomerulonephritis.
The involvement of proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF) in crescentic glomerulonephritis (GN) is well established. Recently the requirement of intrinsic renal cell participation via their production of TNF in crescentic GN was demonstrated. The current studies address the relative contributions of leukocyte and intrinsic renal cell-derived IL-1beta in the induction of TNF production and glomerular injury by studying bone marrow chimeric mice. Leukocyte-derived IL-1beta was critical in the development of crescentic renal injury because IL-1beta(-/-)-->WT (absent leukocyte IL-1beta) chimeric mice had significantly attenuated TNF expression and were protected from the development of crescentic GN. In contrast, WT-->IL-1beta(-/-) chimeric mice (intact leukocyte but absent renal IL-1beta) developed similar TNF expression and crescentic GN to wild-type mice. To determine the cellular target for IL-1 in this model, IL-RI chimeric mice were studied. IL-1RI(-/-)-->WT chimeric (absent leukocyte IL-1RI expression) mice showed no attenuation of crescentic GN, whereas in the absence of renal IL-1RI (WT-->IL-1RI(-/-) chimeras), glomerular TNF expression and the development of crescentic GN were significantly decreased. These studies demonstrate that leukocytes are the major cellular source of IL-1beta, and that IL-1beta acts principally via the IL-1RI on intrinsic renal cells to induce TNF expression and crescentic glomerular injury.
Timoshanko
Jennifer R
JR
Department of Medicine, Centre for Inflammatory Diseases, Monash Medical Centre, Monash University, Clayton, Victoria, Australia. jennifer.timoshanko@med.monash.edu.au
Kitching
A Richard
AR
Iwakura
Yichiro
Y
Holdsworth
Stephen R
SR
Tipping
Peter G
PG
D000818:Animals; D000917:Antibody Formation; D016026:Bone Marrow Transplantation / Q000276:immunology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I; D012712:Serum Globulins / Q000276:immunology; D012756:Sheep; D018183:Transplantation Chimera; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D012712:Serum Globulins; D014409:Tumor Necrosis Factor-alpha