TY - JOUR
T1 - Phospholipase C-β3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells
AU - Bezzerri, Valentino
AU - D'Adamo, Pio
AU - Rimessi, Alessandro
AU - Lanzara, Carmen
AU - Crovella, Sergio
AU - Nicolis, Elena
AU - Tamanini, Anna
AU - Athanasakis, Emmanouil
AU - Tebon, Maela
AU - Bisoffi, Giulia
AU - Drumm, Mitchell L.
AU - Knowles, Michael R.
AU - Pinton, Paolo
AU - Gasparini, Paolo
AU - Berton, Giorgio
AU - Cabrini, Giulio
PY - 2011/4/15
Y1 - 2011/4/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1003535
DO - 10.4049/jimmunol.1003535
M3 - Article
C2 - 21411730
AN - SCOPUS:79955029152
VL - 186
SP - 4946
EP - 4958
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 8
ER -