GLUCOCORTICOID DEFICIENCY INCREASES PHOSPHOLIPASE-A(2) ACTIVITY IN RATS

An important mechanism for the antiinflammatory effect of pharmacologi cal doses of glucocorticoids is the inhibition of arachidonic acid rel ease from phospholipids by phospholipase A2 (PLA2). As a corollary, on e might predict that low endogenous concentrations of glucocorticoids favor inflammatory disease states. Indeed, clinical and experimental o bservations revealed an association between glucocorticoid deficiency and disease states caused by immunological and/or inflammatory mechani sms. The purpose of the present investigation was to study the regulat ion of PLA2 mRNA, protein, and enzyme activity in adrenalectomized (AD X) rats where glucocorticoid concentrations were below physiological l evels. The mRNA of group I and II PLA2 were measured by PCR. Group II PLA2 mRNA was increased by 126+/-9% in lung tissue of ADX rats, wherea s group I PLA2 was increased only by 27+/-1.5%. The increase in group II mRNA in ADX rats was reflected by a corresponding increase of group II PLA2 protein (70-100%) in lung, spleen, liver, and kidney. This in crease was reversed by the administration of exogenous corticosterone. After ADX, the percentage increase in total PLA2 activity was higher than that of mRNA or PLA2 protein, suggesting that the activity of the enzyme was modulated by inhibitors or activators. The concentration o f lipocortin-I, an inhibitor of PLA2 enzyme was strongly correlated wi th the activity of PLA2 in the tissues (lung, spleen, liver, and kidne y). In all these tissues, the concentrations of lipocortin-I declined after ADX. Thus upregulation of PLA2 enzyme and downregulation of lipo cortin-I might account for the enhanced inflammatory response in hypog lucocorticoid states.