The Laboratory for Molecular Pathways in the Resolution of Inflammation, The Department of Human Biology, University of Haifa, Haifa 3498838, Israel.
Int J Mol Sci. 2020 Jul 21;21(14):5166. doi: 10.3390/ijms21145166.
The neutrophil granule protein lactoferrin is cleaved and accumulates in efferocytic macrophages as inflammation is resolved. Two peptides present within a resolution-associated 17 kDa fragment of lactoferrin promote the termination of inflammation in vivo by enhancing murine macrophage reprogramming. Here, we report that these two bioactive tripeptides, phenylalanine-lysine-aspartic acid and phenylalanine-lysine-glutamic acid (FKD and FKE, respectively), inhibit ERK and cJun activation following human macrophage exposure to LPS. In addition, these peptides at low concentrations (1-10 μM) modulate human macrophage reprogramming to an anti-inflammatory/pro-resolving phenotype. This was reflected by inhibition of LPS-induced TNF-α and IL-6 secretion and increased IL-10 levels. Moreover, we found naturally occurring FKE analogs (FKECH and FKECHLA) can recapitulate the activity of the short peptide in regulating macrophage cytokine secretion, whereas a reversed EKF peptide was inert in this respect. Curiously, FKD and FKE also regulated cytokine production by bone marrow-derived mouse macrophages, but in a very different fashion than their effect on human macrophages. Thus, lactoferrin peptides limit pro-inflammatory signaling and cytokine production by LPS-activated human macrophages and thereby enhance the resolution of inflammation.
中性粒细胞颗粒蛋白乳铁蛋白在炎症消退时被切割并积累在吞噬细胞中。乳铁蛋白的一个分辨率相关的 17 kDa 片段内的两个肽促进体内炎症的终止，通过增强鼠巨噬细胞的重编程。在这里，我们报告这两个生物活性三肽，苯丙氨酸-赖氨酸-天冬氨酸和苯丙氨酸-赖氨酸-谷氨酸（分别为 FKD 和 FKE），抑制 ERK 和 cJun 在人巨噬细胞暴露于 LPS 后的激活。此外，这些肽在低浓度（1-10 μM）下调节人巨噬细胞向抗炎/促修复表型的重编程。这反映在抑制 LPS 诱导的 TNF-α 和 IL-6 分泌和增加 IL-10 水平。此外，我们发现天然存在的 FKE 类似物（FKECH 和 FKECHLA）可以再现短肽调节巨噬细胞细胞因子分泌的活性，而反向 EKF 肽在这方面没有活性。奇怪的是，FKD 和 FKE 也调节骨髓来源的小鼠巨噬细胞产生细胞因子，但方式与人巨噬细胞完全不同。因此，乳铁蛋白肽通过限制 LPS 激活的人巨噬细胞中促炎信号和细胞因子的产生，从而增强炎症的消退。
