Tumor Necrosis Factor-α Potentiates Phospholipase A2-Stimulated Release and Metabolism of Arachidonic Acid in Cultured Intestinal Epithelial Cells (INT 407)

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Abstract
Tumor necrosis factor-α (TNF-α), a known pro-inflammatory cytokine, has been suggested to play a role in the pathogenesis of inflammatory bowel disease (IBD) by mediating damage to the intestinal epithelial cells. The present study demonstrates that TNF-α potentiates release and metabolism of l4C-labeled arachidonic acid (14C-AA) in cultured intestinal epithelial cells (INT 407). Although TNF-α on its own was but a weak stimulator of cellular l4C-AA turnover, it significantly potentiated the release of 14C-AA and 14C-labeled prostaglandin E2 (14C-PGE2) after stimulation with three known phospholipase A2 activators: phospholipase C from Clostridium perfringens, the calcium ionophore A23187, and the phorbol ester 4-β-phorbol-12-myristate-13-acetate (PMA). The phospholipase A2 inhibitor quinacrine significantly reduced both AA and PGE2 release after combined stimulation with phospholipase C and TNF-α. In contrast to its effect on the AA turnover, TNF-α did not affect the phospholipase C-stimulated production of platelet-activating factor (PAF-acether). Taken together, these findings indicate that a) TNF-α potentiates phospholipase A2-stimulated AA release from cultured intestinal epithelial cells; b) TNF-α may stimulate phospholipase A2-dependent AA release without affecting the formation of PAF-acether, and c) pretreatment with TNF-α potentiates the formation of PGE2 after stimulation with phospholipase A2 activators. In summary, the present investigation points to the possibility that TNF-α may stimulate intestinal epithelial cells to produce biologically active AA metabolites and that this stimulation may be modulated by components of the intestinal luminal content, like bacterial toxins.