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Resolution-Associated Lactoferrin Peptides Limit LPS Signaling and Cytokine Secretion from Human Macrophages
Aviv Lutaty1, Soaad Soboh1, Sagie Schif-Zuck1
1The Laboratory for Molecular Pathways in the Resolution of Inflammation, The Department of Human Biology, University of Haifa, Haifa 3498838, Israel.
Abstract:
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.
Insights
Lactoferrin peptides phenylalanine-lysine-aspartic acid (FKD) and phenylalanine-lysine-glutamic acid (FKE) reduce inflammation by reprogramming human macrophages. These peptides inhibit pro-inflammatory signaling, promoting the resolution of inflammation.
Area of Science:
- Biochemistry
- Immunology
- Cell Biology
Background:
- Neutrophil lactoferrin is processed into peptides during inflammation resolution.
- Specific lactoferrin-derived peptides, FKD and FKE, are known to promote inflammation termination by reprogramming macrophages.
Purpose of the Study:
- To investigate the anti-inflammatory mechanisms of lactoferrin-derived peptides FKD and FKE in human macrophages.
- To determine the effect of these peptides on macrophage reprogramming and cytokine production.
Main Methods:
- Human macrophages were exposed to lipopolysaccharide (LPS) with or without FKD and FKE peptides.
- ERK and cJun activation were measured.
- Cytokine secretion (TNF-α, IL-6, IL-10) was analyzed.
- Activity of FKE analogs and a reversed peptide were tested.
Main Results:
- FKD and FKE inhibited LPS-induced ERK and cJun activation in human macrophages.
- Low concentrations (1-10 μM) of FKD and FKE induced an anti-inflammatory/pro-resolving macrophage phenotype.
- LPS-induced TNF-α and IL-6 secretion were inhibited, while IL-10 levels increased.
- Naturally occurring FKE analogs mimicked FKE activity, while a reversed peptide was inactive.
- FKD and FKE affected mouse macrophage cytokine production differently than human macrophages.
Conclusions:
- Lactoferrin peptides FKD and FKE limit pro-inflammatory signaling in LPS-activated human macrophages.
- These peptides promote macrophage reprogramming to an anti-inflammatory phenotype, enhancing inflammation resolution.
- Species-specific effects on cytokine production were observed.
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