IL-12p40 and IL-18 in crescentic glomerulonephritis : IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment

Experimental crescentic glomerulonephritis (GN) is characterized by T helper 1 (Th1) directed nephritogenic immune responses and cell-mediated glomerular injury. IL-12p40, the common cytokine chain for both IL-12 and IL-23, is important in the generation and potentially the maintenance of Th1 respon...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology 2005-07, Vol.16 (7), p.2023-2033
Main Authors: KITCHING, A. Richard, TURNER, Amanda L, HOLDSWORTH, Stephen R, WILSON, Gabrielle R. A, SEMPLE, Timothy, ODOBASIC, Dragana, TIMOSHANKO, Jennifer R, O'SULLIVAN, Kim M, TIPPING, Peter G, TAKEDA, Kiyoshi, AKIRA, Shizuo
Format: Article
Language:English
Subjects:
Animals
Anti-Glomerular Basement Membrane Disease - immunology
Biological and medical sciences
Cell Adhesion Molecules - immunology
Chemotaxis, Leukocyte - immunology
Cytokines - immunology
Glomerulonephritis
Immunity, Cellular
Interleukin-12 - genetics
Interleukin-12 - physiology
Interleukin-12 Subunit p40
Interleukin-18 - genetics
Interleukin-18 - physiology
Kidney Glomerulus - immunology
Kidney Glomerulus - pathology
Medical sciences
Mice
Mice, Knockout
Nephrology. Urinary tract diseases
Nephropathies. Renovascular diseases. Renal failure
Protein Subunits - genetics
Protein Subunits - physiology
Th1 Cells - immunology
Th1 Cells - physiology
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Summary:Experimental crescentic glomerulonephritis (GN) is characterized by T helper 1 (Th1) directed nephritogenic immune responses and cell-mediated glomerular injury. IL-12p40, the common cytokine chain for both IL-12 and IL-23, is important in the generation and potentially the maintenance of Th1 responses, whereas IL-18 is a co-factor for Th1 responses that may have systemic and local proinflammatory effects. For testing the hypothesis that both endogenous IL-12p40 and endogenous IL-18 play pathogenetic roles in crescentic GN, accelerated anti-glomerular basement membrane GN was induced in mice genetically deficient in IL-12p40 (IL-12p40-/-), IL-18 (IL-18-/-), or both IL-12p40 and IL-18 (IL-12p40-/-IL-18-/-). Compared with wild-type C57BL/6 mice, IL-12p40-/- mice failed to make a nephritogenic Th1 response and developed markedly reduced crescent formation and renal leukocytic infiltration, despite renal production of chemoattractants and adhesion molecules. IL-18-/- mice developed an intact antigen-specific systemic Th1 response, a similar degree of crescent formation, but fewer glomeruli affected by other severe histologic changes and fewer leukocytes in glomeruli and interstitium. IL-18 was expressed within diseased kidneys. Local production of TNF, IL-1beta, IFN-gamma, CCL3 (MIP-1alpha), and CCL4 (MIP-1beta) was reduced in IL-18-/- mice, demonstrating a local proinflammatory role for IL-18. Combined deletion of IL-12p40 and IL-18 did not result in synergistic effects. Consistent with the hypothesis that inflammation leads to fibrosis, all three groups of deficient mice expressed lower levels of intrarenal TGF-beta1 and/or alpha1(I) procollagen mRNA. These studies demonstrate that in severe experimental crescentic GN, IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 has local proinflammatory roles.
ISSN:1046-6673
1533-3450
DOI:10.1681/ASN.2004121075