Tumor necrosis factor-alpha potentiates phospholipase A2-stimulated release and metabolism of arachidonic acid in cultured intestinal epithelial cells (INT 407).
Tumor necrosis factor-alpha (TNF-alpha), 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-alpha potentiates release and metabolism of 14C-labeled arachidonic acid (14C-AA) in cultured intestinal epithelial cells (INT 407). Although TNF-alpha on its own was but a weak stimulator of cellular 14C-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-beta-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-alpha. In contrast to its effect on the AA turnover, TNF-alpha did not affect the phospholipase C-stimulated production of platelet-activating factor (PAF-acether). Taken together, these findings indicate that a) TNF-alpha potentiates phospholipase A2-stimulated AA release from cultured intestinal epithelial cells; b) TNF-alpha may stimulate phospholipase A2-dependent AA release without affecting the formation of PAF-acether and c) pretreatment with TNF-alpha potentiates the formation of PGE2 after stimulation with phospholipase A2 activators. In summary, the present investigation points to the possibility that TNF-alpha 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.
Gustafson-Svärd
C
C
Dept. of Occupational Medicine, Faculty of Health Sciences, Linköping University, Sweden.
Tagesson
C
C
Boll
R M
RM
Kald
B
B
D016718:Arachidonic Acid / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D050356:Lipid Metabolism; D010741:Phospholipases A / Q000494:pharmacology*; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000494:pharmacology
D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D000001:Calcimycin; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate