Contributions of IL-1β and IL-1α to Crescentic Glomerulonephritis in Mice

Jennifer R. Timoshanko, A. Richard Kitching, Yichiro Iwakura, Stephen R. Holdsworth, Peter G. Tipping

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Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine with two distinct isoforms (IL-1α and IL-1β) that signal through the same IL-1 type I receptor (IL-1RI). Contributions of IL-1β have been demonstrated in human and experimental proliferative glomerulonephritis (GN), but the involvement of IL-1α received little attention. To determine the combined contribution of IL-1α and IL-1β and to dissect the specific contribution of IL-1β, the development of anti-glomerular basement membrane globulin-induced crescentic GN was studied in mice genetically deficient in either the IL-1 receptor type I (IL-1RI-/-), which are unresponsive to both IL-1α and IL-1β, or IL-1β alone (IL-1β-/-). IL-1β-/- mice showed significant reductions in crescent formation and glomerular T cell and macrophage recruitment compared with strain matched controls (WT). No additional reductions of these indices of injury were observed in IL-1RI-/- mice. However, IL-1RI-/- mice showed greater functional renal protection with significantly less proteinuria and reduced serum creatinine compared with IL-1β-/- mice, suggesting a significant contribution of IL-1α to these parameters of injury. IL-1RI-/- mice had lower serum titers of antibody to the nephritogenic antigen (sheep globulin) and reduced glomerular deposition of complement compared with either IL-1β-/- or WT mice. This suggests that in the absence of responses to both IL-1α and IL-1β, attenuation of humoral mediators provides additional functional protection from renal injury that is not seen in the absence of IL-1β alone. These studies indicate that IL-1β but not IL-1α contributes to crescent formation and inflammatory cell recruitment, whereas IL-1α but not IL-1β contributes to humoral mechanisms of glomerular injury.

Original languageEnglish
Pages (from-to)910-918
Number of pages9
JournalJournal of the American Society of Nephrology
Issue number4
Publication statusPublished - 1 Apr 2004

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