Pseudomonas aeruginosa stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of lung inflammatory injury.

Autor:	Ebenezer DL; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, USA., Berdyshev EV; Department of Medicine, National Jewish Health, Denver, Colorado, USA., Bronova IA; Department of Medicine, National Jewish Health, Denver, Colorado, USA., Liu Y; Department of Pharmacology, University of Illinois, Chicago, Illinois, USA., Tiruppathi C; Department of Pharmacology, University of Illinois, Chicago, Illinois, USA., Komarova Y; Department of Pharmacology, University of Illinois, Chicago, Illinois, USA., Benevolenskaya EV; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, USA., Suryadevara V; Department of Medicine, University of Illinois, Chicago, Illinois, USA., Ha AW; Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, USA., Harijith A; Department of Pediatrics, University of Illinois, Chicago, Illinois, USA., Tuder RM; Department of Medicine, University of Colorado, Denver, Colorado, USA., Natarajan V; Department of Pharmacology, University of Illinois, Chicago, Illinois, USA.; Department of Medicine, University of Illinois, Chicago, Illinois, USA., Fu P; Department of Pharmacology, University of Illinois, Chicago, Illinois, USA.
Jazyk:	angličtina
Zdroj:	Thorax [Thorax] 2019 Jun; Vol. 74 (6), pp. 579-591. Date of Electronic Publication: 2019 Feb 05.
DOI:	10.1136/thoraxjnl-2018-212378
Abstrakt:	Introduction: Dysregulated sphingolipid metabolism has been implicated in the pathogenesis of various pulmonary disorders. Nuclear sphingosine-1-phosphate (S1P) has been shown to regulate histone acetylation, and therefore could mediate pro-inflammatory genes expression. Methods: Profile of sphingolipid species in bronchoalveolar lavage fluids and lung tissue of mice challenged with Pseudomonas aeruginosa ( PA ) was investigated. The role of nuclear sphingosine kinase (SPHK)2 and S1P in lung inflammatory injury by PA using genetically engineered mice was determined. Results: Genetic deletion of Sphk2 , but not Sphk1 , in mice conferred protection from PA -mediated lung inflammation. PA infection stimulated phosphorylation of SPHK2 and its localisation in epithelial cell nucleus, which was mediated by protein kinase C (PKC) δ. Inhibition of PKC δ or SPHK2 activity reduced PA -mediated acetylation of histone H3 and H4, which was necessary for the secretion of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-α. The clinical significance of the findings is supported by enhanced nuclear localisation of p-SPHK2 in the epithelium of lung specimens from patients with cystic fibrosis (CF). Conclusions: Our studies define a critical role for nuclear SPHK2/S1P signalling in epigenetic regulation of bacterial-mediated inflammatory lung injury. Targeting SPHK2 may represent a potential strategy to reduce lung inflammatory pulmonary disorders such as pneumonia and CF. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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