鞘氨醇类似物 AAL-R 通过 p38 和 I 型 IFN 信号通路增强 TLR7 介导的树突状细胞反应。
Sphingosine analogue AAL-R increases TLR7-mediated dendritic cell responses via p38 and type I IFN signaling pathways.
机构信息
Department of Surgery, University of Missouri-Columbia, Columbia, MO 65212, USA.
出版信息
J Immunol. 2012 May 15;188(10):4759-68. doi: 10.4049/jimmunol.1102754. Epub 2012 Apr 6.
Abstract
Sphingosine analogues display immunosuppressive activities and thus have therapeutic potential in the treatment of autoimmune diseases. In this study, we investigated the effects of the sphingosine analogue AAL-R (FTY720 derivative) on dendritic cell (DC) response upon TLR stimulation. Unlike its known immunosuppressive activity, AAL-R increased TLR7-mediated DC responses by elevating the levels of MHC class I and costimulatory molecules and type I IFN expression and by enhancing the capacity of DCs to induce CD8(+) T cell proliferation. Importantly, the stimulatory activity of AAL-R was dependent on type I IFN signaling, as type I IFN receptor-deficient DCs failed to respond to AAL-R. Also, AAL-R activated p38 MAPK to increase type I IFN synthesis and TLR7-mediated DC maturation. These findings enhance our understanding of sphingosine regulation of the host immune system, in particular upon pathogenic infections.
摘要
鞘氨醇类似物具有免疫抑制活性，因此在治疗自身免疫性疾病方面具有治疗潜力。在这项研究中，我们研究了鞘氨醇类似物 AAL-R（FTY720 衍生物）对 TLR 刺激后树突状细胞（DC）反应的影响。与已知的免疫抑制活性不同，AAL-R 通过提高 MHC Ⅰ类和共刺激分子的水平以及Ⅰ型 IFN 的表达，并通过增强 DC 诱导 CD8(+)T 细胞增殖的能力，增加 TLR7 介导的 DC 反应。重要的是，AAL-R 的刺激活性依赖于Ⅰ型 IFN 信号，因为缺乏Ⅰ型 IFN 受体的 DC 无法对 AAL-R 产生反应。此外，AAL-R 通过激活 p38 MAPK 来增加Ⅰ型 IFN 的合成和 TLR7 介导的 DC 成熟。这些发现增强了我们对鞘氨醇调节宿主免疫系统的理解，特别是在病原体感染时。
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