Cytoplasmic phospholipase A sub(2) 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: 01.01.1993
• ISSN: 0027-8424

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 super(2+)-dependent cellular phospholipase A sub(2) (cPLA sub(2)). By itself, TNF causes a modest increase in cPLA sub(2) activity, but with the Ca super(2+) ionophore A23187 it provides a strong synergistic action. Within minutes in response to TNF, cPLA sub(2) becomes phosphorylated and in the presence of Ca super(2+) produces a 3- to 4-fold increase in activity. TNF also increases cPLA sub(2) mRNA and protein expression, an estimated 5-fold increase in an 8-hr period. This increase in cPLA sub(2) 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 cPLA sub(2) activation. Our results suggest that the cPLA sub(2) activation may provide a regulatory function and may explain the proinflammatory action of TNF.