title: Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses.
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.
authors: Department of Rheumatology and Inflammation Research, University of Gothenburg, 40530 Gothenburg, Sweden.
authors: Kelly L
authors: KL
authors: Brown
authors: Grace F T
authors: GF
authors: Poon
authors: Darlene
authors: D
authors: Birkenhead
authors: Olga M
authors: OM
authors: Pena
authors: Reza
authors: R
authors: Falsafi
authors: Claes
authors: C
authors: Dahlgren
authors: Anna
authors: A
authors: Karlsson
authors: Johan
authors: J
authors: Bylund
authors: Robert E W
authors: RE
authors: Hancock
authors: Pauline
authors: P
authors: Johnson
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D054804:Cathelicidins