International Immunology, Vol. 16, No. 2, pp. 303-314,
February 2004
© 2004 Japanese Society for Immunology
Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases
1 Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan 2 Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan 3 Department of Medicine and Clinical Science, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan 4 Osaka University, Osaka 565-0871, Japan 5 Core Research for Evolutional Science and Technology, Japan Science and Technology Corp., Tokyo 101-0062, Japan
Correspondence to: T. Naka; E-mail: naka{at}imed3.med.osaka-u.ac.jp
Transmitting editor: T. Watanabe
Suppressor of cytokine signaling (SOCS)-1 is a cytokine-inducible, negative regulatory molecule of Janus kinases (JAK) and its deficiency causes hyper-response to various cytokines. SOCS-1–/– mice spontaneously develop a fatal disease depending on aberrantly activated lymphocytes. Here, we show that partial restoration of SOCS-1 in lymphoid cells rescues SOCS-1–/– mice from the early-onset fatal disease, indicating that SOCS-1 expression in vivo is especially required in lymphocytes. However, SOCS-1 expression in these SOCS-1-restored mutant mice (Eµ-SOCS-1–/– mice) was insufficient for proper down-regulation of its target signaling, and these mice spontaneously exhibit hyperactivation of lymphocytes, an increase in the levels of serum Ig and anti-DNA autoantibodies, and glomerulonephritis with glomerular IgG deposition. These phenotypes resemble those of murine systemic autoimmune diseases, models for systemic lupus erythematosus (SLE). Interestingly, similar phenotypes were also observed in adult female SOCS-1+/– mice, indicating that the autoimmune phenotypes of these mice can be ascribed primarily to the inadequate expression of SOCS-1. In addition, autoimmune phenotypes were not observed in SOCS-1+/–CD4–/– mice, suggesting that autoimmunity is dependent on hyper-activated CD4+ T cells. Our findings also suggest that insufficient expression of SOCS-1 results in impaired function of CD25+CD4+ regulatory T cells, which may contribute to aberrant activation of CD4+ T cells. These findings suggest that dysfunction of SOCS-1 can be a pathogenic factor of systemic autoimmune diseases such as SLE.
Keywords: autoantibody, Janus kinase, STAT-induced STAT inhibitor, suppressor of cytokine signaling, systemic lupus erythematosus
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