Pseudomonas aeruginosa and sPLA2 IB stimulate ABCA1-mediated phospholipid efflux via ERK-activation of PPARalpha-RXR.
Bacterial infection triggers an acute inflammatory response that might alter phospholipid metabolism. We have investigated the acute-phase response of murine lung epithelia to Pseudomonas aeruginosa infection. Ps. aeruginosa triggered secretion of the pro-inflammatory lipase, sPLA2 IB (phospholipase A2 IB), from lung epithelium. Ps. aeruginosa and sPLA2 IB each stimulated basolateral PtdCho (phosphatidylcholine) efflux in lung epithelial cells. Pre-treatment of cells with glyburide, an inhibitor of the lipid-export pump, ABCA1 (ATP-binding cassette transporter A1), attenuated Ps. aeruginosa and sPLA2 IB stimulation of PtdCho efflux. Effects of Ps. aeruginosa and sPLA2 IB were completely abolished in human Tangier disease fibroblasts, cells that harbour an ABCA1 genetic defect. Ps. aeruginosa and sPLA2 IB induced the heterodimeric receptors, PPARa (peroxisome-proliferator-activated receptor-a) and RXR (retinoid X receptor), factors known to modulate ABCA1 gene expression. Ps. aeruginosa and sPLA2 IB stimulation of PtdCho efflux was blocked with PD98059, a p44/42 kinase inhibitor. Transfection with MEK1 (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase 1), a kinase upstream of p44/42, increased PPARa and RXR expression co-ordinately with increased ABCA1 protein. These results suggest that pro-inflammatory effects of Ps. aeruginosa involve release of an sPLA2 of epithelial origin that, in part, via distinct signalling molecules, transactivates the ABCA1 gene, leading to export of phospholipid.
Agassandian
Marianna
M
Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. marianna-agassandian@uiowa.edu
Miakotina
Olga L
OL
Andrews
Matthew
M
Mathur
Satya N
SN
Mallampalli
Rama K
RK
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D054500:Group IB Phospholipases A2; D006801:Humans; D008168:Lung / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000502:physiology*; D010713:Phosphatidylcholines / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism / Q000502:physiology*; D054467:Phospholipases A2; D011552:Pseudomonas Infections / Q000503:physiopathology*; D011550:Pseudomonas aeruginosa; D047488:Retinoid X Receptors / Q000502:physiology*; D013631:Tangier Disease / Q000503:physiopathology; D014162:Transfection; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D005419:Flavonoids; D047493:PPAR alpha; D010713:Phosphatidylcholines; D047488:Retinoid X Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D010741:Phospholipases A; D054500:Group IB Phospholipases A2; C516202:PLA2G1B protein, human; D054467:Phospholipases A2; C516203:Pla2g1b protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D005905:Glyburide