PLCB3 Loss of Function Reduces Pseudomonas aeruginosa-Dependent IL-8 Release in Cystic Fibrosis.

Autor:	Rimessi A; 1 Department of Morphology, Surgery and Experimental Medicine and., Bezzerri V; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy., Salvatori F; 3 Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy., Tamanini A; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy., Nigro F; 1 Department of Morphology, Surgery and Experimental Medicine and., Dechecchi MC; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy., Santangelo A; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy., Prandini P; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy., Munari S; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy., Provezza L; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy., Garreau de Loubresse N; 4 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, Illkirch, France., Muller J; 5 Laboratoire de diagnostic génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; and., Ribeiro CMP; 6 Department of Medicine, and.; 7 Department of Cell Biology and Physiology, Cystic Fibrosis Research Center, Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina., Lippi G; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy., Gambari R; 3 Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy., Pinton P; 1 Department of Morphology, Surgery and Experimental Medicine and., Cabrini G; 2 Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
Jazyk:	angličtina
Zdroj:	American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2018 Oct; Vol. 59 (4), pp. 428-436.
DOI:	10.1165/rcmb.2017-0267OC
Abstrakt:	The lungs of patients with cystic fibrosis (CF) are characterized by an exaggerated inflammation driven by secretion of IL-8 from bronchial epithelial cells and worsened by Pseudomonas aeruginosa infection. To identify novel antiinflammatory molecular targets, we previously performed a genetic study of 135 genes of the immune response, which identified the c.2534C>T (p.S845L) variant of phospholipase C-β3 (PLCB3) as being significantly associated with mild progression of pulmonary disease. Silencing PLCB3 revealed that it potentiates the Toll-like receptor's inflammatory signaling cascade originating from CF bronchial epithelial cells. In the present study, we investigated the role of the PLCB3-S845L variant together with two synthetic mutants paradigmatic of impaired catalytic activity or lacking functional activation in CF bronchial epithelial cells. In experiments in which cells were exposed to P. aeruginosa, the supernatant of mucopurulent material from the airways of patients with CF or different agonists revealed that PLCB3-S845L has defects of 1) agonist-induced Ca 2+ release from endoplasmic reticulum and rise of Ca 2+ concentration, 2) activation of conventional protein kinase C isoform β, and 3) induction of IL-8 release. These results, besides identifying S845L as a loss-of-function variant, strengthen the importance of targeting PLCB3 to mitigate the CF inflammatory response in bronchial epithelial cells without blunting the immune response.
Databáze:	MEDLINE
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