title: Phospholipase C-β3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells.
abstract: Respiratory insufficiency is the major cause of morbidity and mortality in patients affected by cystic fibrosis (CF). An excessive neutrophilic inflammation, mainly orchestrated by the release of IL-8 from bronchial epithelial cells and amplified by chronic bacterial infection with Pseudomonas aeruginosa, leads to progressive tissue destruction. The anti-inflammatory drugs presently used in CF patients have several limitations, indicating the need for identifying novel molecular targets. To address this issue, we preliminarily studied the association of 721 single nucleotide polymorphisms from 135 genes potentially involved in signal transduction implicated in neutrophil recruitment in a cohort of F508del homozygous CF patients with either severe or mild progression of lung disease. The top ranking association was found for a nonsynonymous polymorphism of the phospholipase C-β3 (PLCB3) gene. Studies in bronchial epithelial cells exposed to P. aeruginosa revealed that PLCB3 is implicated in extracellular nucleotide-dependent intracellular calcium signaling, leading to activation of the protein kinase Cα and Cβ and of the nuclear transcription factor NF-κB p65. The proinflammatory pathway regulated by PLCB3 acts by potentiating the Toll-like Receptors' signaling cascade and represents an interesting molecular target to attenuate the excessive recruitment of neutrophils without completely abolishing the inflammatory response.
authors.affiliation: Laboratory of Molecular Pathology, University Hospital of Verona, 37126 Verona, Italy.
authors.forename: Valentino
authors.initials: V
authors.lastname: Bezzerri
authors.forename: Pio
authors.initials: P
authors.lastname: d'Adamo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rimessi
authors.forename: Carmen
authors.initials: C
authors.lastname: Lanzara
authors.forename: Sergio
authors.initials: S
authors.lastname: Crovella
authors.forename: Elena
authors.initials: E
authors.lastname: Nicolis
authors.forename: Anna
authors.initials: A
authors.lastname: Tamanini
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Athanasakis
authors.forename: Maela
authors.initials: M
authors.lastname: Tebon
authors.forename: Giulia
authors.initials: G
authors.lastname: Bisoffi
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Berton
authors.forename: Giulio
authors.initials: G
authors.lastname: Cabrini
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D015870:Gene Expression / Q000187:drug effects; D005787:Gene Frequency; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008856:Microscopy, Fluorescence; D054799:Phospholipase C beta / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D064546:Protein Kinase C beta; D011550:Pseudomonas aeruginosa / Q000502:physiology; D034622:RNA Interference; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D007527:Isoenzymes; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C518039:PLCB3 protein, human; D054799:Phospholipase C beta; D002118:Calcium