Azithromycin suppresses CD4(+) T-cell activation by direct modulation of mTOR activity.
Azithromycin suppresses CD4(+) T-cell activation by direct modulation of mTOR activity.
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阿奇霉素通过直接调节MTOR活性抑制CD4（+）T细胞激活。
DOI：
10.1038/srep07438
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发表时间：
2014-12-11
影响因子：
4.6
通讯作者：
Schmetterer KG
中科院分区：
文献类型：
--
作者：
Ratzinger F;Haslacher H;Poeppl W;Hoermann G;Kovarik JJ;Jutz S;Steinberger P;Burgmann H;Pickl WF;Schmetterer KG
先进的大环内酯类药物，如阿奇霉素(Azm)或克拉霉素(CLM)，是具有免疫调节特性的抗生素。在此，我们试图评估它们在体外对CD4+T细胞活化的影响。用激动型抗CD_3/CD_(28)单抗刺激CD_4~+T细胞，分别加入0.6 /L、2.5 /L、10 /L或40 mg/L。检测细胞增殖、培养上清液中细胞因子水平和细胞活力。采用报告细胞系、流式细胞仪分析、免疫印迹和体外激酶分析等方法评价细胞内信号转导途径。AZM以剂量依赖方式抑制细胞增殖率和CD4+T细胞分泌细胞因子。同样，高浓度的氯仿(40 mg/L)也抑制这些T细胞的功能。对分子信号通路的分析表明，暴露于Azm降低了mTOR下游靶点S6核糖体蛋白的磷酸化。当浓度为40 mg/L时，也可观察到上述作用。用重组mTOR进行的体外激酶研究表明，Azm抑制mTOR活性。与雷帕霉素不同，这种抑制作用不依赖于FKBP12。我们首次发现AZM和CLM通过抑制mTOR活性对CD4+T细胞起免疫抑制作用。我们的研究结果可能对大环内酯类药物的临床应用有所启示。
Advanced macrolides, such as azithromycin (AZM) or clarithromycin (CLM), are antibiotics with immunomodulatory properties. Here we have sought to evaluate their in vitro influence on the activation of CD4+ T-cells. Isolated CD4+ T-cells were stimulated with agonistic anti-CD3/anti-CD28 monoclonal antibodies in the presence of 0.6 mg/L, 2.5 mg/L, 10 mg/L or 40 mg/L AZM or CLM. Cell proliferation, cytokine level in supernatants and cell viability was assessed. Intracellular signaling pathways were evaluated using reporter cell lines, FACS analysis, immunoblotting and in vitro kinase assays. AZM inhibited cell proliferation rate and cytokine secretion of CD4+ T-cells in a dose-dependent manner. Similarly, high concentrations of CLM (40 mg/L) also suppressed these T-cell functions. Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein, a downstream target of mTOR. This effect was also observed at 40 mg/L CLM. In vitro kinase studies using recombinant mTOR showed that AZM inhibited mTOR activity. In contrast to rapamycin, this inhibition was independent of FKBP12. We show for the first time that AZM and to a lesser extent CLM act as immunosuppressive agents on CD4+ T-cells by inhibiting mTOR activity. Our results might have implications for the clinical use of macrolides.
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影响因子：
120.7
作者：
Boomer, Jonathan S.;To, Kathleen;Chang, Kathy C.;Takasu, Osamu;Osborne, Dale F.;Walton, Andrew H.;Bricker, Traci L.;Jarman, Stephen D., II;Kreisel, Daniel;Krupnick, Alexander S.;Srivastava, Anil;Swanson, Paul E.;Green, Jonathan M.;Hotchkiss, Richard S.
通讯作者：
Hotchkiss, Richard S.
影响因子：
3.2
作者：
Ballow, CH;Amsden, GW;Forrest, A
通讯作者：
Forrest, A
影响因子：
56.9
作者：
Lee, KH;Holdorf, AD;Shaw, AS
通讯作者：
Shaw, AS
影响因子：
1.8
作者：
Fietta, A;Merlini, C;Grassi, GG
通讯作者：
Grassi, GG
影响因子：
5.2
作者：
Amsden, GW;Gray, CL
通讯作者：
Gray, CL