Transforming growth factor (TGF)-α and interleukin (IL)-1β are responsible for the healing of gastric lesions through, in part, prostaglandin (PG) generation. We examined the contribution of cytosolic and secretory phospholipase A2s (cPLA2 and sPLA2) to the PG generation by rat gastric epithelial cells in response to both stimuli. Stimulation with TGF-α for 24 h increased cPLA2 and cyclooxygenase (COX)-2 markedly, PGE2 slightly, and type IIA sPLA2 and COX-1 not at all, whereas IL-1β increased sPLA 2 only. Both stimuli synergistically increased PGE2, sPLA2, and the two COXs but not cPLA2. The onset of the PGE2 generation paralleled the sPLA2 release but was apparently preceded by increases in cPLA2 and the two COXs. The increase in PGE2 was impaired by inhibitors for sPLA2 and COX-2 but not COX-1. cPLA2 inhibitors suppressed PGE2 generation by TGF-α alone but not augmentation of PGE2 generation or sPLA2 release by IL-1β in combination with TGF-α. Furthermore, despite an increase in cPLA2 including its phosphorylated form (phosphoserine), A23187-induced arachidonic acid liberation was impaired in the TGF-α/IL-1β-stimulated cells, in which p11, a putative cPLA2 inhibitory molecule, was also increased and co-immunoprecipitated with cPLA2. These results suggest that synergistic stimulation of sPLA2 and COX-2 expression by TGF-α and IL-1β results in an increase in PGE2. Presumably, the preceding cPLA2 expression is not involved in the PGE2 generation, because of impairment of its hydrolytic activity in the stimulated cells.
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