Transforming growth factor‐α stimulates prostaglandin generation through cytosolic phospholipase A2 under the control of p11 in rat gastric epithelial cells

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Abstract
The regulatory effects of transforming growth factor (TGF)‐α on phospholipase A2 (PLA2) isozymes contributing to prostaglandin generation in rat gastric epithelial RGM1 cells were examined. Stimulation with TGF‐α for 24 h time‐dependently induced prostaglandin E2 generation with an increase in cyclo‐oxygenase‐2 protein. The TGF‐α‐induced prostaglandin E2 generation was suppressed by NS‐398, a cyclo‐oxygenase‐2 inhibitor. TGF‐α stimulated the activity and the protein synthesis of cytosolic PLA2 (cPLA2). A time‐dependent increase in cPLA2 protein occurred in parallel with PGE2 generation, which was inhibited by methyl arachidonyl fluorophosphonate (MAFP), a cPLA2 inhibitor. However, no change in activity of secretory PLA2 or Ca+2‐independent PLA2 was observed in the TGF‐α‐stimulated cells. Stimulation with the Ca2+ ionophore A23187 for 10 min induced MAFP‐sensitive arachidonic acid liberation. Interestingly, preincubation with TGF‐α for 24 h diminished A23187‐stimulated arachidonic acid liberation despite the increase in cPLA2 protein. Under the conditions, TGF‐α was found to increase p11, an endogenous cPLA2 suppressor, also known as annexin II light chain. The TGF‐α‐induced increase in p11 was suppressed by tyrphostin AG1478, an inhibitor of tyrosine kinase of epidermal growth factor receptor, which was also found to restore the inhibition by TGF‐α of A23187‐stimulated arachidonic acid liberation. However, TGF‐α did not alter protein levels of annexin II heavy chain. These results suggest that TGF‐α stimulates prostaglandin generation through an increase in cPLA2, the hydrolytic action of which may be under the control of p11. British Journal of Pharmacology (2000) 131, 1004–1010; doi:10.1038/sj.bjp.0703637

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