H1521, a novel derivative of 4-hydroxyquinoline-3-carboxamide, suppresses the development of lupus in mice by inducing Th1 cytokine profile in T cells.
H1521, a novel derivative of 4-hydroxyquinoline-3-carboxamide, suppresses the development of lupus in mice by inducing Th1 cytokine profile in T cells.
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DOI：
10.1016/j.intimp.2010.12.011
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发表时间：
2011-04
影响因子：
5.6
通讯作者：
Zhiyong Xiao;Shao-hui Chen;Wen-xia Zhou;Yongxiang Zhang;Jun Cheng;Ri-fang Yang
中科院分区：
文献类型：
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作者：
Zhiyong Xiao;Shao-hui Chen;Wen-xia Zhou;Yongxiang Zhang;Jun Cheng;Ri-fang Yang
将亲本脾细胞转移到未照射的F1小鼠中诱导慢性移植物抗宿主病（GVHD），其特征在于产生Th 2细胞因子和类似于系统性红斑狼疮（SLE）的免疫复合物介导的肾小球肾炎。在慢性移植物抗宿主病狼疮模型上研究了新的4-羟基喹啉-3-甲酰胺衍生物H1521的作用。将H1521给予慢性GVHD小鼠10周。监测肾病症状并检测脾脏中细胞因子的表达。为了阐明H1521对CD 4 +T细胞的直接作用，分离CD 4 +T细胞并与H1521在中性和Th 1或Th 2驱动条件下体外共培养。H1521（32 mg/kg）使慢性GVHD小鼠的蛋白尿发生率降低50%。还观察到狼疮症状改善和肾组织病理学损伤改善。H1521给药对Th 1细胞因子IL-2和IFN-γ或Th 2细胞因子IL-4和IL-10 mRNA表达的影响很小。相反，在慢性GVHD小鼠中，伴刀豆球蛋白A刺激的脾细胞产生的严重缺陷的IFN-γ被H1521完全恢复。与此一致，用H1521（32 mg/kg）处理，降低的T-bet mRNA表达变得正常化。体外研究表明，H1521能促进Th 1分化的CD 4 +T细胞分泌IFN-γ，促进Th 1分化的CD 4 +T细胞分泌IFN-γ。而H1521对初始或Th 2分化的CD 4 +T细胞IL-4分泌无影响。结论：H1521可诱导CD 4 +T细胞产生Th 1型细胞因子，对Th 2型免疫疾病具有潜在的治疗价值。
Transferring parental splenocytes into unirradiated F1 mice induces a chronic graft-versus-host disease (GVHD), characterized by the production of Th2 cytokines and immunocomplex-mediated glomerulonephritis resembling systemic lupus erythematosus (SLE). The effects of H1521, a new derivative of 4-hydroxyquinoline-3-carboxamide, were investigated in chronic GVHD lupus model. H1521 was administered to chronic GVHD mice for 10weeks. Nephritic symptoms were monitored and cytokine expression in the spleen was detected. To clarify the direct effect of H1521 on CD4+T cell, CD4+T cells were isolated and co-cultured with H1521 under neutral and Th1 or Th2 driving conditions in vitro. H1521 (32mg/kg) reduced the incidence of proteinuria by 50% in chronic GVHD mice. Ameliorated lupus symptoms and improved renal histopathology damage were also observed. Administration of H1521 had little impact on Th1 cytokine IL-2 and IFN-gamma or Th2 cytokine IL-4 and IL-10 mRNA expression. In contrast, severely deficient IFN-gamma production by concanavalin A-stimulated spleen cells in chronic GVHD mice was completely restored by H1521. In accordance with this, decreased T-bet mRNA expression became normalized with H1521 (32mg/kg) treatment. In addition, in vitro studies demonstrated that H1521 preferentially favored Th1 differentiation in CD4+T cell and promoted IFN-gamma secretion in Th1 differential CD4+T cell. However, IL-4 secretion in naive or Th2 differential CD4+T cell was unaffected by H1521. In conclusion, H1521 can induce Th1 cytokine profile in CD4+T cells and has possible therapeutic value in Th2-predominant immune diseases.