Antimicrobial Peptide hLF1-11 Directs Granulocyte-Macrophage Colony-Stimulating Factor-Driven Monocyte Differentiation toward Macrophages with Enhanced Recognition and Clearance of Pathogens
Antimicrobial Peptide hLF1-11 Directs Granulocyte-Macrophage Colony-Stimulating Factor-Driven Monocyte Differentiation toward Macrophages with Enhanced Recognition and Clearance of Pathogens
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DOI：
10.1128/aac.00652-09
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发表时间：
2010-02-01
影响因子：
4.9
通讯作者：
Nibbering, Peter H.
中科院分区：
文献类型：
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作者：
van der Does, Anne M.;Bogaards, Sylvia J. P.;Nibbering, Peter H.
人乳铁蛋白衍生肽hLF1-11在体外显示出抗菌活性，对动物耐抗生素细菌和耐氟康唑白色念珠菌感染有效。然而，这些活动背后的机制在很大程度上仍不清楚。由于hLF1-11在体外生理盐浓度下无效，我们认为调节免疫系统是该肽的另一种作用机制。我们研究了hLF1-11是否影响人单核-巨噬细胞分化，并测定了由此产生的巨噬细胞的抗菌活性。单核细胞用GM-CSF在不同时间间隔的hLF1-11、对照肽或生理盐水中培养7天。第6天，用脂多糖（LPS）、脂壁酸（LTA）或热杀白色念珠菌刺激细胞24 h。随后，测定培养上清液中细胞因子水平、病原体识别受体表达和这些巨噬细胞的抗菌活性。结果表明，在gm - csf驱动的分化过程中，单核细胞短时间暴露于hLF1-11足以引导单核细胞向巨噬细胞亚群分化，其特征是产生促炎性和抗炎性细胞因子，并增加对微生物结构的反应性。此外，这些巨噬细胞对白色念珠菌和金黄色葡萄球菌非常有效。综上所述，hLF1-11可以引导gm - csf驱动的单核细胞向巨噬细胞分化，并增强巨噬细胞的效应功能。
The human lactoferrin-derived peptide hLF1-11 displays antimicrobial activities in vitro and is effective against infections with antibiotic-resistant bacteria and fluconazole-resistant Candida albicans in animals. However, the mechanisms underlying these activities remain largely unclear. Since hLF1-11 is ineffective in vitro at physiological salt concentrations, we suggested modulation of the immune system as an additional mechanism of action of the peptide. We investigated whether hLF1-11 affects human monocyte-macrophage differentiation and determined the antimicrobial activities of the resulting macrophages. Monocytes were cultured for 7 days with GM-CSF in the presence of hLF1-11, control peptide, or saline for various intervals. At day 6, the cells were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or heat-killed C. albicans for 24 h. Thereafter, the levels of cytokines in the culture supernatants, the expression of pathogen recognition receptors, and the antimicrobial activities of these macrophages were determined. The results showed that a short exposure of monocytes to hLF1-11 during GM-CSF-driven differentiation is sufficient to direct differentiation of monocytes toward a macrophage subset characterized by both pro-and anti-inflammatory cytokine production and increased responsiveness to microbial structures. Moreover, these macrophages are highly effective against C. albicans and Staphylococcus aureus. In conclusion, hLF1-11 directs GM-CSF-driven differentiation of monocytes toward macrophages with enhanced effector functions.