Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses

J Immunol. 2011 May 1;186(9):5497-505. doi: 10.4049/jimmunol.1002508. Epub 2011 Mar 25.

Abstract

The human cathelicidin peptide, LL-37, is a host defense peptide with a wide range of immunomodulatory activities and modest direct antimicrobial properties. LL-37 can exert both pro- and anti-inflammatory effects and can modulate the proinflammatory responses of human peripheral blood monocytes and epithelial cells. In this study, we evaluated the effect of LL-37 on mouse bone marrow-derived macrophages (BMDM) and tissue macrophages in vitro and in vivo. LL-37 dramatically reduced TNF-α and NO levels produced by LPS and IFN-γ-polarized M1-BMDM and slightly reduced reactive oxygen species production by these cells. LL-37 did not affect the ability of IL-4-polarized M2-BMDM to upregulate arginase activity, although it did inhibit LPS-induced TNF-α secretion in these cells. LL-37 did not compromise the ability of M1-polarized BMDM to phagocytose and kill bacteria and did not affect the uptake of apoptotic neutrophils by M2-polarized BMDM. However, LL-37-treated M1-BMDM were more efficient at suppressing tumor growth in vitro. LL-37 significantly reduced LPS-induced TNF-α secretion in ex vivo alveolar macrophages, whereas its effect on peritoneal macrophages was much less dramatic. Effective inhibition of LPS-induced TNF-α secretion by alveolar macrophages also occurred in vivo when LL-37 was administered by intratracheal injection. This demonstrates a selective ability of LL-37 to decrease M1-BMDM, M2-BMDM, and tissue macrophage production of the proinflammatory cytokine TNF-α in response to LPS while leaving other crucial anti-inflammatory M1 and M2 macrophage functions unaltered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / immunology*
  • Antimicrobial Cationic Peptides / metabolism
  • Cell Differentiation / immunology
  • Cell Separation
  • Cytokines / biosynthesis
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Macrophages / cytology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide / biosynthesis
  • Nitric Oxide / immunology
  • Phagocytosis / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antimicrobial Cationic Peptides
  • Cytokines
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • ropocamptide