title: Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells.
abstract: We examined the hypothesis that stromal fibroblasts modulate the ability of endothelial cells (EC) to recruit lymphocytes in a site-specific manner. PBL were perfused over HUVEC that had been cultured with fibroblasts isolated from the inflamed synovium or the skin of patients with rheumatoid arthritis or osteoarthritis, or from normal synovium, with or without exposure to the inflammatory cytokines TNF-alpha+IFN-gamma. Fibroblasts from inflamed synovium, but no others, caused unstimulated HUVEC to bind flowing lymphocytes. This adhesion was supported by alpha(4)beta(1)-VCAM-1 interaction and stabilised by activation of PBL through CXCR4-CXCL12. Antibody neutralisation of IL-6 during co-culture effectively abolished the ability of EC to bind lymphocytes. Cytokine-stimulated EC supported high levels of lymphocyte adhesion, through the presentation of VCAM-1, E-selectin and chemokine(s) acting through CXCR3. Interestingly, co-culture with dermal fibroblasts caused a marked reduction in cytokine-induced adhesion, while synovial fibroblasts had variable effects depending on their source. In the dermal co-cultures, neutralisation of IL-6 or TGF-beta caused partial recovery of cytokine-induced lymphocyte adhesion; this was complete when both were neutralised. Exogenous IL-6 was also found to inhibit response to TNF-alpha+IFN-gamma. Normal stromal fibroblasts appear to regulate the cytokine-sensitivity of vascular endothelium, while fibroblasts associated with chronic inflammation bypass this and develop a directly inflammatory phenotype. Actions of IL-6 might be pro-inflammatory or anti-inflammatory, depending on the local milieu.
authors.affiliation: Centre for Cardiovascular Sciences, The Medical School, The University of Birmingham, Birmingham, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGettrick
authors.forename: Emily
authors.initials: E
authors.lastname: Smith
authors.forename: Andrew
authors.initials: A
authors.lastname: Filer
authors.forename: Stephen
authors.initials: S
authors.lastname: Kissane
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D019040:E-Selectin / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D054367:Receptors, CXCR3 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000998:Antiviral Agents; D054377:Chemokine CXCL12; D019040:E-Selectin; D007371:Interferon-gamma; D015850:Interleukin-6; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000093242:Interleukin-6 Inhibitors; C515187:CXCR3 protein, human; C508600:IL6 protein, human