Fujimoto Minoru, Tsutsui Hiroko, Xinshou Ouyang, Tokumoto Masanori, Watanabe Dai, Shima Yoshihito, Yoshimoto Tomohiro, Hirakata Hideki, Kawase Ichiro, Nakanishi Kenji, Kishimoto Tadamitsu, Naka Tetsuji
Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
Int Immunol. 2004 Feb;16(2):303-14. doi: 10.1093/intimm/dxh030.
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.
细胞因子信号转导抑制因子（SOCS）-1是一种细胞因子诱导的Janus激酶（JAK）负调控分子，其缺陷会导致对各种细胞因子的过度反应。SOCS-1基因敲除（-/-）小鼠会自发发展出一种依赖异常激活淋巴细胞的致命疾病。在此，我们表明淋巴细胞中SOCS-1的部分恢复可使SOCS-1基因敲除小鼠免于早发性致命疾病，这表明体内SOCS-1的表达在淋巴细胞中尤为必要。然而，在这些SOCS-1恢复的突变小鼠（E（微）-SOCS-1基因敲除小鼠）中，SOCS-1的表达不足以对其靶信号进行适当的下调，这些小鼠会自发出现淋巴细胞过度激活、血清Ig和抗DNA自身抗体水平升高以及伴有肾小球IgG沉积的肾小球肾炎。这些表型类似于小鼠系统性自身免疫疾病，即系统性红斑狼疮（SLE）的模型。有趣的是，在成年雌性SOCS-1杂合（+/-）小鼠中也观察到了类似的表型，这表明这些小鼠的自身免疫表型主要可归因于SOCS-1表达不足。此外，在SOCS-1（+/-）CD4基因敲除小鼠中未观察到自身免疫表型，这表明自身免疫依赖于过度激活的CD4（+）T细胞。我们的研究结果还表明，SOCS-1表达不足会导致CD25（+）CD4（+）调节性T细胞功能受损，这可能导致CD4（+）T细胞异常激活。这些发现表明，SOCS-1功能障碍可能是系统性自身免疫疾病如SLE的致病因素。
