title: Proteinase-activated receptor-2 modulates human macrophage differentiation and effector function.
abstract: Proteinase-activated receptor-2 (PAR-2) was shown to influence immune regulation; however, its role in human macrophage subset development and function has not been addressed. Here, PAR-2 expression and activation was investigated on granulocyte macrophage (GM)-CSF(M1) and macrophage (M)-CSF(M2) macrophages. In both macrophages, the PAR-2-activating peptide, SLIGKV, increased PAR-2 expression and regulated TNF-α and IL-10 secretion in a manner similar to LPS. In addition, HLA-DR on M1 cells also increased. Monocytes matured to an M1 phenotype in the presence of SLIGKV had reduced cell area, and released less TNF-α after LPS challenge compared with vehicle (P < 0.05, n = 3). Cells matured to an M2 phenotype with SLIGKV also had a reduced cell area and made significantly more TNF-α after LPS exposure compared to vehicle (P < 0.05, n = 3) with reduced IL-10 secretion (P < 0.05, n = 3). Thus, PAR-2 activation on macrophage subsets regulates HLA-DR and PAR-2 surface expression, and drives cytokine production. In contrast, PAR-2 activation during M1 or M2 maturation induces altered cell morphology and skewing of phenotype, as evidenced by cytokine secretion. These data suggest a complex role for PAR-2 in macrophage biology and may have implications for macrophage-driven disease in which proteinase-rich environments can influence the immune process directly.
authors.affiliation: 1Centre for Musculoskeletal Science, School of Science, University of the West of Scotland, Paisley, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Steven
authors.forename: Anne
authors.initials: A
authors.lastname: Crilly
authors.forename: John C
authors.initials: JC
authors.lastname: Lockhart
authors.forename: William R
authors.initials: WR
authors.lastname: Ferrell
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D009842:Oligopeptides / Q000494:pharmacology*; D044464:Receptor, PAR-2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006684:HLA-DR Antigens; D008070:Lipopolysaccharides; D009842:Oligopeptides; D044464:Receptor, PAR-2; D014409:Tumor Necrosis Factor-alpha; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Macrophage subsets; proteinase activated receptor-2