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.
Highlights
The engulfment of apoptotic polymorphonuclear cells (PMN) by macrophages during the resolution of inflammation is considered to be a hallmark and a major fate-determining event for these cells [1,2,3,4]
We examined three major signal transduction pathways previously found to be involved in cytokine production, following LPS exposure: ERK1/2, P38MAPK and cJun [18,19]
Previous reports have indicated that lactoferrin is cleaved to several short peptides that act on varioPursecveilolutysprespofrrotms hmavueriinned,ibcaotveidnethaantdlahcutomfearnrionrigsicnle[a1v3–ed15t,o20s]e. vDeurarlinsghobratcpteerpiatildinesfetchtaiotna,cat oLnf fvragrimouesntcewllitthyp2e2skfDroamwmasuprrinevei,obuosvlyindeeasncrdibheudminanboovrigniena[n1d3–h1u5m,20a]n
Summary
The engulfment of apoptotic polymorphonuclear cells (PMN) by macrophages during the resolution of inflammation is considered to be a hallmark and a major fate-determining event for these cells [1,2,3,4]. The phagocytosis of apoptotic cells and phagolysosome maturation reportedly result in the degradation of the apoptotic cell content [5]. Neutrophil-derived defensins are preserved and transferred from engulfed apoptotic PMN to the phagolysosomes in the engulfing macrophage and limit intracellular growth of M. tuberculosis [6]. Lactoferrin (Lf), an iron-binding glycoprotein from the transferrin family with a molecular weight of 78 kDa, is found in various body fluids like milk, colostrum, saliva, tears, and mucus secretions, as well as in neutrophil secondary granules [7]. Neutrophil degranulation is the main source of Lf in blood [8]. Several peptides within Lf have previously been shown to have distinct bioactivities that in some cases differ from the parent protein [7,12,13,14]
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