Center for Gastrointestinal Biology and Diseases, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
J Immunol. 2011 Apr 15;186(8):4649-55. doi: 10.4049/jimmunol.1003888. Epub 2011 Mar 7.
Regulation of innate inflammatory responses against the enteric microbiota is essential for the maintenance of intestinal homeostasis. Key participants in innate defenses are macrophages. In these studies, the basic leucine zipper protein, NFIL3, is identified as a regulatory transcription factor in macrophages, controlling IL-12 p40 production induced by bacterial products and the enteric microbiota. Exposure to commensal bacteria and bacterial products induced NFIL3 in cultured macrophages and in vivo. The Il12b promoter has a putative DNA-binding element for NFIL3. Basal and LPS-activated NFIL3 binding to this site was confirmed by chromatin immunoprecipitation. LPS-induced Il12b promoter activity was inhibited by NFIL3 expression and augmented by NFIL3-short hairpin RNA in an Il12b-bacterial artificial chromosome-GFP reporter macrophage line. Il12b inhibition by NFIL3 does not require IL-10 expression, but a C-terminal minimal repression domain is necessary. Furthermore, colonic CD11b(+) lamina propria mononuclear cells from Nfil3(-/-) mice spontaneously expressed Il12b mRNA. Importantly, lower expression of NFIL3 was observed in CD14(+) lamina propria mononuclear cells from Crohn's disease and ulcerative colitis patients compared with control subjects. Likewise, no induction of Nfil3 was observed in colons of colitis-prone Il10(-/-) mice transitioned from germ-free to a conventional microbiota. In conclusion, these experiments characterize NFIL3 as an Il12b transcriptional inhibitor. Interactions of macrophages with the enteric microbiota induce NFIL3 to limit their inflammatory capacity. Furthermore, altered intestinal NFIL3 expression may have implications for the pathogenesis of experimental and human inflammatory bowel diseases.
先天炎症反应对肠道微生物群的调节对于维持肠道内环境稳定至关重要。先天防御的关键参与者是巨噬细胞。在这些研究中，碱性亮氨酸拉链蛋白 NFIL3 被鉴定为巨噬细胞中的一种调节转录因子，控制细菌产物和肠道微生物群诱导的 IL-12 p40 产生。共栖细菌和细菌产物的暴露诱导培养的巨噬细胞和体内的 NFIL3。Il12b 启动子具有 NFIL3 的假定 DNA 结合元件。通过染色质免疫沉淀证实了 NFIL3 对该位点的基础和 LPS 激活结合。NFIL3 表达抑制 LPS 诱导的 Il12b 启动子活性，并在 Il12b-细菌人工染色体-GFP 报告巨噬细胞系中通过 NFIL3-short hairpin RNA 增强。NFIL3 对 Il12b 的抑制不需要 IL-10 表达，但需要 C 末端最小抑制结构域。此外，Nfil3(-/-) 小鼠结肠 CD11b(+) 固有层单核细胞自发表达 Il12b mRNA。重要的是，与对照相比，克罗恩病和溃疡性结肠炎患者的 CD14(+) 固有层单核细胞中 NFIL3 的表达较低。同样，在从无菌到常规微生物群过渡的易患结肠炎的 Il10(-/-) 小鼠的结肠中未观察到 Nfil3 的诱导。总之，这些实验将 NFIL3 表征为 Il12b 的转录抑制剂。巨噬细胞与肠道微生物群的相互作用诱导 NFIL3 以限制其炎症能力。此外，肠道 NFIL3 表达的改变可能对实验性和人类炎症性肠病的发病机制有影响。
