title: IL-8 dictates glycosaminoglycan binding and stability of IL-18 in cystic fibrosis.
abstract: Dysregulation of airway inflammation contributes to lung disease in cystic fibrosis (CF). Inflammation is mediated by inflammatory cytokines, including IL-8, which illustrates an increase in biological half-life and proinflammatory activity when bound to glycosaminoglycans (GAGs). The aim of this project was to compare IL-8 and IL-18 for their relative stability, activity, and interaction with GAGs, including chondroitin sulfate, hyaluronic acid, and heparan sulfate, present in high quantities in the lungs of patients with CF. Bronchoalveolar lavage fluid was collected from patients with CF (n = 28), non-CF controls (n = 14), and patients with chronic obstructive pulmonary disease (n = 12). Increased levels of IL-8 and reduced concentrations of IL-18 were detected in bronchial samples obtained from CF individuals. The low level of IL-18 was not a defect in IL-18 production, as the pro- and mature forms of the molecule were expressed and produced by CF epithelial cells and monocytes. There was, however, a marked competition between IL-8 and IL-18 for binding to GAGs. A pronounced loss of IL-18 binding capacity occurred in the presence of IL-8, which displaced IL-18 from these anionic-matrices, rendering the cytokine susceptible to proteolytic degradation by neutrophil elastase. As a biological consequence of IL-18 degradation, reduced levels of IL-2 were secreted by Jurkat T lymphocytes. In conclusion, a novel mechanism has been identified highlighting the potential of IL-8 to determine the fate of other inflammatory molecules, such as IL-18, within the inflammatory milieu of the CF lung.
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland. emerreeves@rcsi.ie
authors.forename: Emer P
authors.initials: EP
authors.lastname: Reeves
authors.forename: Michael
authors.initials: M
authors.lastname: Williamson
authors.forename: Barry
authors.initials: B
authors.lastname: Byrne
authors.forename: David A
authors.initials: DA
authors.lastname: Bergin
authors.forename: Stephen G J
authors.initials: SG
authors.lastname: Smith
authors.forename: Peter
authors.initials: P
authors.lastname: Greally
authors.forename: Richard
authors.initials: R
authors.lastname: O'Kennedy
authors.forename: Shane J
authors.initials: SJ
authors.lastname: O'Neill
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
mesh_terms: D000293:Adolescent; D001667:Binding, Competitive / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000276:immunology; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000737:chemistry / Q000378:metabolism; D020382:Interleukin-18 / Q000737:chemistry* / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000502:physiology*; D019169:Jurkat Cells; D011485:Protein Binding / Q000276:immunology; D055550:Protein Stability; D015854:Up-Regulation / Q000276:immunology
chemical_list: D006025:Glycosaminoglycans; D018836:Inflammation Mediators; D020382:Interleukin-18; D016209:Interleukin-8