title: Monocyte Subsets Coregulate Inflammatory Responses by Integrated Signaling through TNF and IL-6 at the Endothelial Cell Interface.
abstract: Two major monocyte subsets, CD14+CD16-(classical) and CD14+/dimCD16+(nonclassical/intermediate), have been described. Each has different functions ascribed in its interactions with vascular endothelial cells (EC), including migration and promoting inflammation. Although monocyte subpopulations have been studied in isolated systems, their influence on EC and on the course of inflammation has been ignored. In this study, using unstimulated or cytokine-activated EC, we observed significant differences in the recruitment, migration, and reverse migration of human monocyte subsets. Associated with this, and based on their patterns of cytokine secretion, there was a difference in their capacity to activate EC and support the secondary recruitment of flowing neutrophils. High levels of TNF were detected in cocultures with nonclassical/intermediate monocytes, the blockade of which significantly reduced neutrophil recruitment. In contrast, classical monocytes secreted high levels of IL-6, the blockade of which resulted in increased neutrophil recruitment. When cocultures contained both monocyte subsets, or when conditioned supernatant from classical monocytes cocultures (IL-6hi) was added to nonclassical/intermediate monocyte cocultures (TNFhi), the activating effects of TNF were dramatically reduced, implying that when present, the anti-inflammatory activities of IL-6 were dominant over the proinflammatory activities of TNF. These changes in neutrophil recruitment could be explained by regulation of E-selectin on the cocultured EC. This study suggests that recruited human monocyte subsets trigger a regulatory pathway of cytokine-mediated signaling at the EC interface, and we propose that this is a mechanism for limiting the phlogistic activity of newly recruited monocytes.
authors.affiliation: Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Myriam
authors.identifier: 0000-0002-3567-1731
authors.initials: M
authors.lastname: Chimen
authors.affiliation: Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Clara M
authors.identifier: 0000-0003-3218-7941
authors.initials: CM
authors.lastname: Yates
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Helen M
authors.identifier: 0000-0002-5950-8840
authors.initials: HM
authors.lastname: McGettrick
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Lewis S C
authors.identifier: 0000-0002-5087-6305
authors.initials: LS
authors.lastname: Ward
authors.affiliation: Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Harrison
authors.affiliation: Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Bonita
authors.initials: B
authors.lastname: Apta
authors.affiliation: Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Lea H
authors.initials: LH
authors.lastname: Dib
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Imhof
authors.affiliation: Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Paul
authors.identifier: 0000-0003-4610-8909
authors.initials: P
authors.lastname: Harrison
authors.affiliation: Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Gerard B
authors.identifier: 0000-0002-5935-2831
authors.initials: GB
authors.lastname: Nash
authors.affiliation: Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; g.e.rainger@bham.ac.uk.
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
mesh_terms: D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D009000:Monocytes / Q000276:immunology*; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha