Abstract
Gastric epithelial cells liberate prostaglandin E(2) in response to cytokines as part of the process of healing of gastric lesions. Treatment of the rat gastric epithelial cell line RGM1 with transforming growth factor-alpha and interleukin-1beta leads to synergistic release of arachidonate and production of prostaglandin E(2). Results with highly specific and potent phospholipase A(2) inhibitors and with small interfering RNA show that cytosolic phospholipase A(2)-alpha and group IIA secreted phospholipase A(2) contribute to arachidonate release from cytokine-stimulated RGM1 cells. In the late phase of arachidonate release, group IIA secreted phospholipase A(2) is induced (detected at the mRNA and protein levels), and the action of cytosolic phospholipase A(2)-alpha is required for this induction. Results with RGM1 cells and group IIA secreted phospholipase A(2)-transfected HEK293 cells show that the group IIA phospholipase acts prior to externalization from the cells. RGM1 cells also express group XIIA secreted phospholipase A(2), but this enzyme is not regulated by cytokines nor does it contribute to arachidonate release. The other eight secreted phospholipases A(2) were not detected in RGM1 cells at the mRNA level. These results clearly show that cytosolic and group IIA secreted phospholipases A(2) work together to liberate arachidonate from RGM1 cell phospholipids in response to cytokines.
Highlights
The mouse and human genomes contain genes encoding 10 distinct secreted phospholipases A2 (PLA2) [7, 8] suggesting multiple physiological functions for sPLA2s
A key feature of this study is that we study arachidonate release in a cell line that has not been treated exogenously with sPLA2s or transfected with sPLA2s
Group XIIA sPLA2 is present in these cells, but its level does not change with cytokine treatment
Summary
The mouse and human genomes contain genes encoding 10 distinct secreted PLA2s (sPLA2s) [7, 8] suggesting multiple physiological functions for sPLA2s. In order to explore the contribution of group IIA sPLA2 and cPLA2-␣ to arachidonate release and PGE2 production in cytokine-stimulated RGM1 cells, studies with highly selective, and potent inhibitors were carried out.
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