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Breast milk lactoferrin regulates gene expression by binding bacterial DNA CpG motifs but not genomic DNA promoters in model intestinal cells

机译:母乳乳铁蛋白通过结合细菌DNA CpG基序而不是模型肠细胞中的基因组DNA启动子来调节基因表达

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摘要

High-affinity binding of DNA by lactoferrin (LF) is an established phenomenon, but the biologic function of this interaction remains unclear. LF is an abundant breast milk protein (12.5-87.5 mu mol/L) and is resistant to digestion in the infant gut. Regulation of gene expression by LF appears to be a major activity, particularly in modulating immune responses. We hypothesized that LF binding to DNA is a mechanism of gene regulation and aimed to identify the mechanism and physiologic sites of this activity. Our studies focused on two major biologic compartments of DNA: LF binding to proinflammatory bacterial DNA sequences (CpG motifs) in extracellular compartments and LF binding to genomic DNA promoters in the nucleus. LF 0.5 mmol/L inhibited CpG motif-induced nuclear factor-kappa B (NF-kappa B) activation and interleukin (IL)-8 and IL-12 cytokine gene transcription in B cells. Intestinal epithelial cells were unresponsive to CpG motifs. However, significant LF transferred across M cell-like monolayers, specialized epithelial cells that transcytose intact macromolecules to underlying B-cell follicles in the intestine. LF did not activate gene expression by binding to putative response elements in epithelial and lymphoid cells. Nor did LF bind to putative response elements specifically in gel-shift assays. No nuclear localization of LF was detected in green fluorescent protein (GFP) tagging experiments. We conclude that breast milk LF regulates gene expression by binding CpG motifs extracellularly, with follicular B cells in C the infant intestine a likely target.
机译:乳铁蛋白(LF)与DNA的高亲和力结合是一种既定现象,但这种相互作用的生物学功能仍不清楚。 LF是一种丰富的母乳蛋白(12.5-87.5μmol / L),对婴儿肠道的消化具有抵抗力。 LF调节基因表达似乎是一项主要活动,尤其是在调节免疫反应中。我们假设LF与DNA的结合是基因调控的机制,旨在确定这种活动的机制和生理部位。我们的研究集中在DNA的两个主要生物区室上:LF与细胞外区室中的促炎细菌DNA序列(CpG基序)结合以及LF与细胞核中的基因组DNA启动子结合。 LF 0.5 mmol / L抑制了CpG基序诱导的B细胞核因子-κB(NF-κB)活化以及白介素(IL)-8和IL-12细胞因子基因转录。肠上皮细胞对CpG基序无反应。但是,大量的LF跨M细胞样单层转移,这是专门化的上皮细胞,可将完整的大分子转入胞内的潜在B细胞卵泡。 LF不能通过与上皮细胞和淋巴样细胞中的假定反应元件结合来激活基因表达。 LF也没有特异性地结合于凝胶位移测定中的推定反应元件。在绿色荧光蛋白(GFP)标记实验中未检测到LF的核定位。我们得出的结论是,母乳LF通过在细胞外结合CpG基序来调节基因表达,而婴儿肠C中的卵泡B细胞可能是靶标。

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