Journal of the American Society of Nephrology
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J Am Soc Nephrol 15:919-927, 2004
© 2004 American Society of Nephrology


BASIC SCIENCE

Modulation of Interferon-Induced Genes by Lipoxin Analogue in Anti–Glomerular Basement Membrane Nephritis

Takamoto Ohse*, Tatsuru Ota*, Niamh Kieran{dagger}, Catherine Godson{dagger}, Koei Yamada*, Tetsuhiro Tanaka*, Toshiro Fujita* and Masaomi Nangaku*

*Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan; {dagger}Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Mater Misericordiae Hospital, and Dublin Molecular Medicine Center, Dublin, Ireland.

Corrrespondence to Dr. Masaomi Nangaku, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-8648; Fax: 81-3-5800-8806; E-mail: mnangaku-tky{at}umin.ac.jp

ABSTRACT. Immune complex deposition is associated with the accumulation of neutrophils, which play an important role in the various immune-mediated diseases. A novel anti-inflammatory agent, the lipoxin A (LXA) analogue (15-epi-16-(FPhO)-LXA-Me)), a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A4 (ATLa), was used in experimental anti–glomerular basement membrane (GBM) antibody nephritis in mice. ATLa was administered before the induction of the disease, and 2 h later, the animals were killed. ATLa reduced the infiltrating neutrophils and nitrotyrosine staining in glomeruli. Subsequent changes of gene expression in the early phase were evaluated, and 5674 genes were present under the basal conditions in kidneys from normal mice; 54 upregulated genes and 25 downregulated genes were detected in anti-GBM nephritis. Eighteen of these upregulated genes were those induced by IFN-{gamma}. Real-time quantitative PCR analysis confirmed the results of the microarrays. To investigate a role of IFN-{gamma} in neutrophil infiltration, anti-GBM nephritis was induced in IFN-{gamma} knockout mice. The number of infiltrating neutrophils in these mice did not differ from those in wild-type mice. Also examined were CD11b expression on neutrophils from mice treated with ATLa by flow cytometry, but suppression of this adhesion molecule was not observed. Neutrophil infiltration was successfully inhibited by ATLa in the early phase of murine anti-GBM nephritis. Microarray analysis detected the change of mRNA expression in anti-GBM nephritis and demonstrated amelioration of various genes by ATLa, which may provide a clue to the development of novel therapeutic approaches in immune renal injury.




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