title: Interleukin-4 and lipopolysaccharide synergize to induce vascular cell adhesion molecule-1 expression in human lung microvascular endothelial cells.
abstract: Recent studies suggest that increased vascular cell adhesion molecule-1 (VCAM-1) expression on vascular endothelium in bronchial mucosa biopsies correlates with interleukin-4 (IL-4) levels in bronchiolar lavage fluid of allergic asthmatics. The severity of asthma in patients allergic to house dust mite has also been shown to correlate with lipopolysaccharide (LPS), rather than allergen, concentration in dust. We hypothesized that to induce effective VCAM-1 expression in human lung microvascular endothelial cells (HLMVEC), IL-4 may require the presence of a co-stimulus such as LPS. To test this hypothesis we measured, by enzyme-linked immunosorbent assay, induction of cell adhesion molecule expression on, and human eosinophil adhesion to, cultured HLMVEC monolayers pretreated with IL-4 alone or combined with LPS. IL-4 synergized with LPS to induce VCAM-1 expression at 24, 48, or 72 h, whereas IL-4 alone induced expression at 72 h only. IL-4 did not induce expression of intercellular adhesion molecule-1 or E-selectin or alter LPS-induced expression of either. Pre-exposure of HLMVEC to LPS or IL-4 (1 h), followed by IL-4 or LPS, respectively (23 h), also induced VCAM-1 expression. Eosinophil adhesion to HLMVEC monolayers treated with IL-4 and LPS together, but not alone, significantly (P < 0.001) increased from 9.6 +/- 1.5% (control) to 26.9 +/- 3.3% and was inhibited by a monoclonal antibody against the VCAM-1 ligand, very late antigen-4. Analysis of VCAM-1 mRNA revealed synergism between IL-4 and LPS which may, in part, contribute to enhanced VCAM-1 expression. These results suggest that the presence of a co-stimulus such as LPS may be necessary for IL-4 to effectively induce VCAM-1 expression in lung microvasculature.
authors.affiliation: Applied Pharmacology, Thoracic Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Blease
authors.forename: J
authors.initials: J
authors.lastname: Seybold
authors.forename: I M
authors.initials: IM
authors.lastname: Adcock
authors.forename: P G
authors.initials: PG
authors.lastname: Hellewell
authors.forename: A
authors.initials: A
authors.lastname: Burke-Gaffney
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D019040:E-Selectin / Q000235:genetics; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D004804:Eosinophils / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply*; D008833:Microcirculation / Q000502:physiology; D018375:Neutrophil Activation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
chemical_list: D019040:E-Selectin; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4