Cytoplasmic phospholipase A2 activity and gene expression are stimulated by tumor necrosis factor: dexamethasone blocks the induced synthesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 10; pp. 4475 - 4479
• Main Authors: HOECK, W. G, RAMESHA, C. S, CHANG, D. J, FAN, N, HELLER, R. A
• Format: Journal Article
• Language: English
• Published: Washington, DC National Acad Sciences 15.05.1993; National Academy of Sciences of the United States of America
• Subjects: Arachidonic Acid - pharmacology; Biological and medical sciences; Calcimycin - pharmacology; Calcium - metabolism; Cytoplasm - enzymology; Dexamethasone - pharmacology; Enzyme Induction - drug effects; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; HeLa Cells; Humans; In Vitro Techniques; Inflammation; Molecular and cellular biology; Phospholipases A - metabolism; Phospholipases A2; Phosphorylation; RNA, Messenger - genetics; Signal Transduction; Tumor Necrosis Factor-alpha - pharmacology; Human; Dexamethasone; Enzyme; Cytokine; Antiinflammatory agent; Inflammation; Arachidonic acid; Gene expression; Glucocorticoid; Hela cell line; Phospholipase A; Signal transduction; Tumor necrosis factor; Mechanism of action; Cytoplasm
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.10.4475

The interaction of tumor necrosis factor alpha (TNF) with its two membrane-bound receptors initiates intracellular events in which arachidonic acid and its derivatives are involved. In HeLa cells, TNF treatment induces an arachidonic acid-selective, Ca(2+)-dependent cellular phospholipase A2 (cPLA2). By itself, TNF causes a modest increase in cPLA2 activity, but with the Ca2+ ionophore A23187 it provides a strong synergistic action. Within minutes in response to TNF, cPLA2 becomes phosphorylated and in the presence of Ca2+ produces a 3- to 4-fold increase in activity. TNF also increases cPLA2 mRNA and protein expression, an estimated 5-fold increase in an 8-hr period. This increase in cPLA2 activity occurs, therefore, in a biphasic time-dependent manner. Dexamethasone, known to antagonize the action of TNF, is here shown to inhibit TNF-induced gene expression and to prevent the second phase of increase in cPLA2 activation. Our results suggest that the cPLA2 activation may provide a regulatory function and may explain the proinflammatory action of TNF.