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Blockade of IL-18 Receptor Signaling Delays the Onset of Autoimmune Disease in MRL-Fas^lpr Mice¹

Department of Hematology, Nephrology and Rheumatology, Kinki University School of Medicine, Osaka, Japan

Autoimmune disease in Fas-deficient MRL-Fas^lpr mice is dependent on infiltrating autoreactive leukocytes and autoantibodies, and IFN- plays an important role in the pathogenesis. As IL-18 is capable of inducing IFN- production in T cells, we hypothesized that signaling through IL-18R is involved in the pathogenesis. To investigate the impact of IL-18 in this autoimmune disease, we generated an MRL-Fas^lpr strain deficient in IL-18R. Compared with the wild-type strain, IL-18R-deficient MRL-Fas^lpr mice survived longer and showed a significant reduction in renal pathology, including glomerular IgG deposits, proteinuria, and serum anti-DNA Abs. Intrarenal transcripts encoding IFN-, TNF-, IL-12, and IL-10, which have been linked to nephritis, were all markedly reduced. Skin lesions, lymphadenopathy, and lung pathology characteristic of the MRL-Fas^lpr mouse disease were diminished in IL-18R-deficient MRL-Fas^lpr mice. Thus, we conclude that IL-18R signaling is critical to the pathogenesis of autoimmune disease in MRL-Fas^lpr mice.

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