Intracellular secretory leukoprotease inhibitor modulates inositol 1,4,5-triphosphate generation and exerts an anti-inflammatory effect on neutrophils of individuals with cystic fibrosis and chronic obstructive pulmonary disease.
Adult, Anti-Inflammatory Agents, Calcium, Cell Degranulation, Chemotaxis, Cystic Fibrosis, Cytoskeleton, Cytosol, Female, Humans, Immunologic Factors, Inositol 1, 4, 5-Trisphosphate, Intracellular Space, Male, Models, Biological, Neutrophil Activation, Neutrophils, Oxidation-Reduction, Pulmonary Disease, Chronic Obstructive, Recombinant Proteins, Secretory Leukocyte Peptidase Inhibitor
This work was supported by the Medical Research Charities Group/Health Research Board, Science Foundation Ireland (Grant no. 11/RFP/BMT/3094), the US Alpha One Foundation, and the Program for Research in Third Level Institutes (PRTLI) administered by the Higher Education Authority and Science Foundation Ireland.
Secretory leukoprotease inhibitor (SLPI) is an anti-inflammatory protein present in respiratory secretions. Whilst epithelial cell SLPI is extensively studied, neutrophil associated SLPI is poorly characterised. Neutrophil function including chemotaxis and degranulation of proteolytic enzymes involves changes in cytosolic calcium (Ca(2+)) levels which is mediated by production of inositol 1,4,5-triphosphate (IP3) in response to G-protein-coupled receptor (GPCR) stimuli. The aim of this study was to investigate the intracellular function of SLPI and the mechanism-based modulation of neutrophil function by this antiprotease. Neutrophils were isolated from healthy controls (n = 10), individuals with cystic fibrosis (CF) (n = 5) or chronic obstructive pulmonary disease (COPD) (n = 5). Recombinant human SLPI significantly inhibited fMet-Leu-Phe (fMLP) and interleukin(IL)-8 induced neutrophil chemotaxis (P < 0.05) and decreased degranulation of matrix metalloprotease-9 (MMP-9), hCAP-18, and myeloperoxidase (MPO) (P < 0.05). The mechanism of inhibition involved modulation of cytosolic IP3 production and downstream Ca(2+) flux. The described attenuation of Ca(2+) flux was overcome by inclusion of exogenous IP3 in electropermeabilized cells. Inhibition of IP3 generation and Ca(2+) flux by SLPI may represent a novel anti-inflammatory mechanism, thus strengthening the attractiveness of SLPI as a potential therapeutic molecule in inflammatory airway disease associated with excessive neutrophil influx including CF, non-CF bronchiectasis, and COPD.
Medicine and Health Sciences
Reeves EP, Banville N, Ryan DM, O'Reilly N, Bergin DA, Pohl K, Molloy K, McElvaney OJ, Alsaleh K, Aljorfi A, Kandalaft O, O'Flynn E, Geraghty P, O'Neill SJ, McElvaney NG. Intracellular secretory leukoprotease inhibitor modulates inositol 1,4,5-triphosphate generation and exerts an anti-inflammatory effect on neutrophils of individuals with cystic fibrosis and chronic obstructive pulmonary disease. BioMed Research International. 2013; 2013: 560141.
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