Blockade of IL-18 receptor signaling delays the onset of autoimmune disease in MRL-Faslpr mice.
Autoimmune disease in Fas-deficient MRL-Faslpr mice is dependent on infiltrating autoreactive leukocytes and autoantibodies, and IFN-gamma plays an important role in the pathogenesis. As IL-18 is capable of inducing IFN-gamma 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-Faslpr strain deficient in IL-18Ralpha. Compared with the wild-type strain, IL-18Ralpha-deficient MRL-Faslpr 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-gamma, TNF-alpha, 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-Faslpr mouse disease were diminished in IL-18Ralpha-deficient MRL-Faslpr mice. Thus, we conclude that IL-18Ralpha signaling is critical to the pathogenesis of autoimmune disease in MRL-Faslpr mice.
Department of Hematology, Nephrology and Rheumatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan. kinoshita@int3.med.kindai.ac.jp
Koji
K
Kinoshita
Toshiaki
T
Yamagata
Yuji
Y
Nozaki
Masafumi
M
Sugiyama
Shinya
S
Ikoma
Masanori
M
Funauchi
Akihisa
A
Kanamaru
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000517:prevention & control; D001806:Blood Urea Nitrogen; D016207:Cytokines / Q000235:genetics; D006942:Hypergammaglobulinemia / Q000517:prevention & control; D007371:Interferon-gamma / Q000502:physiology; D053727:Interleukin-18 Receptor alpha Subunit; D007668:Kidney / Q000473:pathology; D008168:Lung / Q000473:pathology; D008206:Lymphatic Diseases / Q000517:prevention & control; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011507:Proteinuria / Q000517:prevention & control; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000502:physiology*; D053724:Receptors, Interleukin-18; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D019014:fas Receptor / Q000235:genetics*
D016207:Cytokines; C508573:Il18r1 protein, mouse; D053727:Interleukin-18 Receptor alpha Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D019014:fas Receptor; D007371:Interferon-gamma