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

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

*Monash Medical Centre, Clayton, Victoria, Australia; and Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Corresponding to Professor Peter Tipping, Dept of Medicine, Monash Medical Center, 246 Clayton Road, Clayton, Victoria, 3168, Australia. Phone: 61-3-9594-5547; Fax: 61-3-9594-6495; E-mail: peter.tipping{at}monash.edu.au

ABSTRACT. Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine with two distinct isoforms (IL-1 and IL-1) that signal through the same IL-1 type I receptor (IL-1RI). Contributions of IL-1 have been demonstrated in human and experimental proliferative glomerulonephritis (GN), but the involvement of IL-1 has received little attention. To determine the combined contribution of IL-1 and IL-1 and to dissect the specific contribution of IL-1, 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-1 and IL-1, or IL-1 alone (IL-1-/-). IL-1-/- 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-1-/- mice, suggesting a significant contribution of IL-1 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-1-/- or WT mice. This suggests that in the absence of responses to both IL-1 and IL-1, attenuation of humoral mediators provides additional functional protection from renal injury that is not seen in the absence of IL-1 alone. These studies indicate that IL-1 but not IL-1 contributes to crescent formation and inflammatory cell recruitment, whereas IL-1 but not IL-1 contributes to humoral mechanisms of glomerular injury.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673