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The IL-23/Th17 Axis Contributes to Renal Injury in Experimental Glomerulonephritis

Hans-Joachim Paust^*, Jan-Eric Turner^*, Oliver M. Steinmetz^*, Anett Peters^*, Felix Heymann, Christoph Hölscher, Gunter Wolf, Christian Kurts, Hans-Willi Mittrücker^||, Rolf A.K. Stahl^* and Ulf Panzer^*

^* III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Institute for Molecular Medicine and Experimental Immunology, Universitätsklinikum Bonn, Bonn, Germany; Junior Research Group Molecular Infection Biology, Research Center Borstel, Borstel, Germany; Klinik für Innere Medizin III, Klinikum der Friedrich-Schiller-Universität, Jena, Germany; and ^|| Institut für Immunologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Correspondence: Dr. Ulf Panzer, Universitätsklinikum Hamburg-Eppendorf, III Medizinische Klinik, Martinistrasse 52, 20246 Hamburg, Germany; Phone: +49-40-42803-1557; Fax: +49-40-42803-9036; E-mail: panzer{at}uke.uni-hamburg.de

Received for publication May 30, 2008. Accepted for publication November 25, 2008.

T cells infiltrate the kidney in both human and experimental glomerulonephritis, and several lines of evidence indicate that T cell-mediated tissue damage plays an important role in the immunopathogenesis of renal inflammatory diseases. However, the functions of the different T cell subsets, particularly the recently identified interleukin-17 (IL-17)-producing T cells (Th17 cells), are incompletely understood in glomerulonephritis. Here, we identified renal IL-17-producing T cells in the T cell-mediated model of nephrotoxic nephritis in mice. In vitro, IL-17 enhanced the production of the proinflammatory chemokines CCL2/MCP-1, CCL3/MIP-1, and CCL20/LARC, which are implicated in the recruitment of T cells and monocytes, in mouse mesangial cells. To determine the function of Th17 cells in renal inflammation, we induced nephrotoxic nephritis in IL-23 p19^–/– mice, which have reduced numbers of Th17 cells, and in IL-17^–/– mice, which are deficient in the effector cytokine IL-17 itself. In comparison with nephritic wild-type mice, IL-23 p19^–/– mice demonstrated less infiltration of Th17 cells, and both IL-23 p19^–/– and IL-17^–/– mice developed less severe nephritis as measured by renal function, albuminuria, and frequency of glomerular crescent formation. These results demonstrate that the IL-23/IL-17 pathway significantly contributes to renal tissue injury in experimental glomerulonephritis. Targeting the IL-23/Th17 axis may be a promising therapeutic strategy for the treatment of proliferative and crescentic glomerulonephritis.

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