Lipid phosphate phosphatase-1 regulates lysophosphatidic acid-induced calcium release, NF-kappaB activation and interleukin-8 secretion in human bronchial epithelial cells.
LPA (lysophosphatidic acid), a potent bioactive phospholipid, elicits diverse cellular responses through activation of the G-protein-coupled receptors LPA1-LPA4. LPA-mediated signalling is partially regulated by LPPs (lipid phosphate phosphatases; LPP-1, -2 and -3) that belong to the phosphatase superfamily. This study addresses the role of LPPs in regulating LPA-mediated cell signalling and IL-8 (interleukin-8) secretion in HBEpCs (human bronchial epithelial cells). Reverse transcription-PCR and Western blotting revealed the presence and expression of LPP-1-3 in HBEpCs. Exogenous [3H]oleoyl LPA was hydrolysed to [3H]-mono-oleoylglycerol. Infection of HBEpCs with an adenoviral construct of human LPP-1 for 48 h enhanced the dephosphorylation of exogenous LPA by 2-3-fold compared with vector controls. Furthermore, overexpression of LPP-1 partially attenuated LPA-induced increases in the intracellular Ca2+ concentration, phosphorylation of IkappaB (inhibitory kappaB) and translocation of NF-kappaB (nuclear factor-kappaB) to the nucleus, and almost completely prevented IL-8 secretion. Infection of cells with an adenoviral construct of the mouse LPP-1 (R217K) mutant partially attenuated LPA-induced IL-8 secretion without altering LPA-induced changes in intracellular Ca2+ concentration, phosphorylation of IkappaB, NF-kappaB activation or IL-8 gene expression. Our results identify LPP-1 as a key regulator of LPA signalling and IL-8 secretion in HBEpCs. Thus LPPs could represent potential targets in regulating leucocyte infiltration and airway inflammation.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21222, USA.
Yutong
Y
Zhao
Peter V
PV
Usatyuk
Rhett
R
Cummings
Bahman
B
Saatian
Donghong
D
He
Tonya
T
Watkins
Andrew
A
Morris
Ernst W M
EW
Spannhake
David N
DN
Brindley
Viswanathan
V
Natarajan
D000256:Adenoviridae; D001120:Arginine / Q000235:genetics / Q000502:physiology; D001980:Bronchi / Q000166:cytology*; D002118:Calcium / Q000378:metabolism*; D002457:Cell Extracts / Q000737:chemistry; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000201:enzymology* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D016040:Lung Transplantation; D008239:Lysine / Q000235:genetics / Q000502:physiology; D008246:Lysophospholipids / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists; D014019:Tissue Donors
D002457:Cell Extracts; D016209:Interleukin-8; D008246:Lysophospholipids; D016328:NF-kappa B; D049368:Receptors, Lysophosphatidic Acid; D001120:Arginine; C112948:lipid phosphate phosphatase; D010711:Phosphatidate Phosphatase; D008239:Lysine; C032881:lysophosphatidic acid; D002118:Calcium