Pseudomonas aeruginosa and sPLA2 IB stimulate ABCA1-mediated phospholipid efflux via ERK-activation of PPARα-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 Psendomonas aeruginosa infection. Ps. aeruginosa triggered secretion of the pro-inflammatory lipase, sPLA(2) IB (phospholiparse A(2) IB), from lung epithelium. Ps. aeruginosa and sPLA(2) IB each stimulated basolateral PtdCho (phosphatidylcholine) efflux in lung epithelial cells. Pre-treatment of cells with glyburide, an inhibitor of the lipid-export pump, ABCAI (ATP-binding cassette transporter Al), attenuated Ps. aeruginosa and sPLA, IB stimulation of PtdCho efflux. Effects of Ps. aeruginosa and sPLA(2) IB were completely abolished in human Tangier disease fibroblasts, cells that harbour an ABCA1 genetic defect. Ps. aeruginosa and sPLA(2) IB induced the heterodimeric receptors, PPAR alpha (peroxisome-prol iferator-activated receptor-alpha) and RXR (retinoid X receptor), factors known to modulate ABCA1 gene expression. Ps. aeruginosa and sPLA(2) 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 upstrearn ofp44/42, increased PPAR alpha and RXR expression co-ordinately with increased ABCAI protein. These results suggest that pro-inflammatory effects of Ps. aeruginosa involve release of an sPLA(2) of epithelial origin that, in part, via distinct signalling molecules, transactivates the ABCAI gene, leading to export of phospholipid.