Resolution-associated lactoferrin peptides limit lps signaling and cytokine secretion from human macrophages

Aviv Lutaty, Soaad Soboh, Sagie Schif-Zuck, Amiram Ariel

Research output: Contribution to journalArticlepeer-review

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 proinflammatory signaling and cytokine production by LPS-activated human macrophages and thereby enhance the resolution of inflammation.

Original languageEnglish
Article number5166
Pages (from-to)1-14
Number of pages14
JournalInternational Journal of Molecular Sciences
Volume21
Issue number14
DOIs
StatePublished - 2020

Bibliographical note

Funding Information:
Funding: The study was partially funded by the Israel Science Foundation: grants No. 534/09 and No. 678/13.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Cytokines
  • LPS
  • Lactoferrin
  • Macrophages
  • Resolution of inflammation

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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