Phospholipase C-β3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells

Valentino Bezzerri, Pio D'Adamo, Alessandro Rimessi, Carmen Lanzara, Sergio Crovella, Elena Nicolis, Anna Tamanini, Emmanouil Athanasakis, Maela Tebon, Giulia Bisoffi, Mitchell L. Drumm, Michael R. Knowles, Paolo Pinton, Paolo Gasparini, Giorgio Berton, Giulio Cabrini

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4946-4958
Number of pages13
JournalJournal of Immunology
Volume186
Issue number8
DOIs
Publication statusPublished - Apr 15 2011

ASJC Scopus subject areas

  • Immunology

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