Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
Eur J Immunol. 2012 Dec;42(12):3310-21. doi: 10.1002/eji.201142213. Epub 2012 Oct 26.
Intestinal epithelial cells (IECs) normally promote the development of gut resident tolerogenic dendritic cells (DCs) and regulatory T cells, but how this process is altered in inflammatory bowel disease is not well characterized. Recently, we published that the cell injury signal ATP modulates IEC chemokine responses to the TLR5 ligand flagellin and exacerbates colitis in the presence of flagellin. We hypothesized that ATP switches these IECs from tolerogenic to proinflammatory, enhancing DC activation and immune responses to commensal antigens. Here, we report that ATP enhanced murine IEC production of KC, IL-6, TGF-β, and thymic stromal lymphopoietin in response to TLR1/2 stimulation by Pam(3) CSK(4) (PAM). Moreover, supernatants from IECs stimulated with ATP+PAM enhanced expression of CD80 on bone marrow derived dendritic cells, and increased their production of IL-12, IL-6, IL-23, TGF-β, and aldh1a2, suggesting a Th1/Th17 polarizing environment. DCs conditioned by stressed IECs stimulated an enhanced recall response to flagellin and supported the expansion of IFN-γ(+) and IL-17(+) memory T cells. Lastly, colonic administration of nonhydrolysable ATP increased production of IL-6 and Cxcl1 (KC) by IECs. These findings indicate that ATP influences the response of IECs to TLR ligands and biases the maturation of DCs to become inflammatory.
肠上皮细胞（IECs）通常促进肠道驻留的耐受性树突状细胞（DCs）和调节性 T 细胞的发育，但在炎症性肠病中这一过程如何改变尚不清楚。最近，我们发表了一篇论文，指出细胞损伤信号 ATP 调节 IEC 趋化因子对 TLR5 配体鞭毛蛋白的反应，并在鞭毛蛋白存在的情况下加剧结肠炎。我们假设 ATP 将这些 IEC 从耐受性转变为促炎状态，增强 DC 激活和对共生抗原的免疫反应。在这里，我们报告说，ATP 增强了小鼠 IEC 对 TLR1/2 刺激 Pam（3）CSK（4）（PAM）的 KC、IL-6、TGF-β 和胸腺基质淋系生成素的产生。此外，用 ATP+PAM 刺激的 IEC 的上清液增强了骨髓来源的树突状细胞上 CD80 的表达，并增加了它们对 IL-12、IL-6、IL-23、TGF-β 和 aldh1a2 的产生，提示 Th1/Th17 极化环境。应激 IEC 条件化的 DC 刺激对鞭毛蛋白的增强记忆反应，并支持 IFN-γ（+）和 IL-17（+）记忆 T 细胞的扩增。最后，结肠给予非水解型 ATP 增加了 IEC 对 IL-6 和 Cxcl1（KC）的产生。这些发现表明，ATP 影响 IEC 对 TLR 配体的反应，并使 DC 成熟偏向于炎症。
