Interleukin-10 stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is required for the proliferative but not the antiinflammatory effects of the cytokine
Interleukin-10 stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is required for the proliferative but not the antiinflammatory effects of the cytokine
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DOI：
10.1074/jbc.271.27.16357
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发表时间：
1996-07-05
影响因子：
4.8
通讯作者：
Foxwell, BMJ
中科院分区：
文献类型：
--
作者：
Crawley, JB;Williams, LM;Foxwell, BMJ
Interleukin-10 (IL-10) 是脂多糖刺激的单核细胞以及 T 细胞和 B 细胞生长辅助因子产生促炎单核因子的强大抑制剂。IL-10 连接至其同源受体引发的信号转导级联仍有待阐明。在此，我们证明在原代单核细胞和 D36 细胞系中， IL-10 快速、短暂地刺激与酶的 p85 亚基相关的磷脂酰肌醇 5-激酶活性，IL-10 还在两种细胞类型中激活 p70 S6 激酶，这两种激酶的激活对磷脂酰肌醇 3-激酶抑制剂渥曼青霉素敏感，p70 S6 激酶的激活也受到抑制 由免疫抑制药物雷帕霉素引起。雷帕霉素和渥曼青霉素均抑制IL-10诱导的D36细胞增殖，但相反，对细胞因子对脂多糖刺激的单核细胞的抗炎作用没有影响，用另一种磷脂酰肌醇获得了IL-10对D36增殖和脂多糖刺激的单核细胞抑制的类似结果 3-激酶抑制剂，LY294002，这表明磷脂酰肌醇3-激酶和p70 S6激酶的激活参与IL-10的增殖功能，并且其他尚未表征的途径影响对单核细胞的抑制作用，表明多种不同的信号传导途径介导IL-10的各种多效性活性。此外，这些发现表明，将来有可能在不破坏细胞因子其他功能的情况下调节 IL-10 的抗炎作用以获得治疗效果。
Interleukin-10 (IL-10) is a powerful suppressor of the proinflammatory monokine production by lipopolysaccharide-stimulated monocytes as well as a T- and B-cell growth cofactor, The signal transduction cascades initiated by IL-10 ligation to its cognate receptor remain to be elucidated, Here, we demonstrate that in both primary monocytes and the D36 cell line, IL-10 rapidly and transiently stimulated phosphatidylinositol 5-kinase activity associated with the p85 subunit of the enzyme, IL-10 also activated p70 S6 kinase in both cell types, The activation of both of these kinases was sensitive to wortmannin, an inhibitor of phosphatidylinositol 3-kinase, The activation of p70 S6 kinase was also inhibited by the immunosuppressive drug rapamycin. Both rapamycin and wortmannin inhibited the IL-10-induced proliferation of D36 cells but in contrast had no effect on the antiinflammatory effects of the cytokine on lipopolysaccharide-stimulated monocytes, Similar results on D36 proliferation and lipopolysaccharide stimulated monocyte inhibition by IL-10 were obtained with another phosphatidylinositol 3-kinase inhibitor, LY294002, This suggests that the activation of phosphatidylinositol 3-kinase and p70 S6 kinase is involved in the proliferative functions of IL-10 and that other as yet uncharacterized pathways affect the suppressive effects on monocytes, indicating that multiple and distinct signaling pathways mediate the various pleiotropic activities of IL-10. Furthermore, these findings suggest that it may be possible in the future to modulate the antiinflammatory effects of IL-10 for therapeutic benefit without disrupting other functions of the cytokine.