Cytosolic phospholipase A2α enhances mouse mortality induced by Pseudomonas aeruginosa pulmonary infection via interleukin 6

Autor: Laurent Guillemot, Lhousseine Touqui, Erwan Pernet, Dominique Leduc, Michel Chignard, Yongzheng Wu, Mathieu Medina
Přispěvatelé: Défense innée et inflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], This work was supported by the French Association of Cystic Fibrosis 'Vaincre la Mucoviscidose', and the 'Legs Poix' Foundation., We are grateful to B. Polack and B. Toussaint (Université Joseph Fourier, Grenoble, France) for providing the CHA strain, and to G. Eberl (Institut Pasteur, Paris, France) for providing IL6−/− mice., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Rok vydání: 2014
Předmět:
Lung Diseases
Male
MAPK/ERK pathway
MESH: Macrophages
Alveolar
medicine.medical_treatment
p38 Mitogen-Activated Protein Kinases
MESH: Mice
Knockout
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Biochemistry
MESH: Lung Diseases
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Arachidonate 15-Lipoxygenase
MESH: Animals
Enzyme Inhibitors
Extracellular Signal-Regulated MAP Kinases
MESH: Extracellular Signal-Regulated MAP Kinases
Mice
Knockout
MESH: Immunoblotting
medicine.diagnostic_test
MESH: Pseudomonas Infections
General Medicine
respiratory system
3. Good health
Survival Rate
medicine.anatomical_structure
Cytokine
MESH: Enzyme Inhibitors
Host-Pathogen Interactions
Pseudomonas aeruginosa
MESH: Pseudomonas aeruginosa
MESH: Mice
Inbred CFTR
Female
Tumor necrosis factor alpha
Acute lung infection
MESH: Cyclooxygenase 2
medicine.symptom
Bronchoalveolar Lavage Fluid
MESH: Survival Rate
MESH: Group IV Phospholipases A2
Immunoblotting
Inflammation
Arachidonic Acids
Lung injury
Biology
Cell Line
Proinflammatory cytokine
Species Specificity
MESH: Mice
Inbred C57BL
Macrophages
Alveolar
medicine
Animals
Mice
Inbred CFTR
MESH: Arachidonic Acids
MESH: Species Specificity
Pseudomonas Infections
Lung
Interleukin-6
MESH: Bronchoalveolar Lavage Fluid
Group IV Phospholipases A2
MESH: Host-Pathogen Interactions
Cytosolic phospholipase A2α (cPLA2α)
MESH: Interleukin-6
[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Molecular biology
IL6
MESH: Male
MESH: Cell Line
Mice
Inbred C57BL
MESH: p38 Mitogen-Activated Protein Kinases
Bronchoalveolar lavage
Cyclooxygenase 2
Immunology
MESH: Arachidonate 15-Lipoxygenase
MESH: Female
Zdroj: Biochimie
Biochimie, Elsevier, 2014, 107, pp.95-104. ⟨10.1016/j.biochi.2014.08.018⟩
Biochimie, 2014, 107, pp.95-104. ⟨10.1016/j.biochi.2014.08.018⟩
ISSN: 0300-9084
Popis: International audience; Pseudomonas aeruginosa pulmonary infection is a leading cause of death in numerous diseases such as cystic fibrosis (CF). The host cytosolic phospholipase A2α (cPLA2α) releases lipid mediators that play an important role in the pathogenesis of diseases, but its role in lung injury induced by P. aeruginosa infection is still obscure. Using an animal model of P. aeruginosa lung infection, we showed that the CHA strain of P. aeruginosa was more potent than the PAK strain in inducing mouse mortality and lung injury, and that both mouse mortality and lung injury were reduced in cPLA2α(-/-) mice as compared to cPLA2α(+/+) mice. This was accompanied by decreased levels of IL6 but not other inflammatory cytokines (IL1β, KC and TNFα) in the bronchoalveolar lavage fluids (BALFs) of cPLA2α(-/-) mice. Given that CFTR(-/-) mice exhibit increased cPLA2α activation in the lung, the role of cPLA2α was further examined in this lung infection model. Compared to littermates, P. aeruginosa infection caused increased mortality in CFTR(-/-) mice with high IL6 levels in BALFs, which was attenuated by pharmacological inhibition of cPLA2α. In addition, compared to IL6(-/-) mice, an enhanced mortality was also observed in P. aeruginosa infected IL6(+/+) mice. Since alveolar macrophages (AMs) are the primary inflammatory cytokine source in the lung, murine AMs cell line (MH-S) were used to investigate the signalling pathways involved in this process. Incubation of MH-S cells with P. aeruginosa induced IL6 production, which was mediated by MAPKs ERK/p38 and was abolished by cPLA2α inhibitors. Furthermore, among cPLA2 downstream signalling pathways, only 15-lipoxygenase (15-LOX) and cyclooxygenase-2 (COX-2) were proven to participate in this P. aeruginosa-induced IL6 expression. Based on all these observations, we conclude that cPLA2α enhances P. aeruginosa-induced animal lethality in part via IL6 induction and that MAPKs ERK/p38, 15-LOX and COX-2 signalling pathways were involved in this process.
Databáze: OpenAIRE
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