title: Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases.
abstract: 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 (E( micro )-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.
authors.affiliation: Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Ouyang
authors.initials: O
authors.lastname: Xinshou
authors.forename: Masanori
authors.initials: M
authors.lastname: Tokumoto
authors.forename: Dai
authors.initials: D
authors.lastname: Watanabe
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Shima
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirakata
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018417:Th1 Cells / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D015704:CD4 Antigens; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D015375:Receptors, Interleukin-2; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma