New mechanisms for effects of anti-inflammatory glucocorticoids

Suppression of inflammatory prostaglandins (PGs) is a major factor in the anti-inflammatory action of the glucocorticoids. The molecular mechanisms whereby this inhibition occurs are complex, but considerable progress has been made in recent years towards their understanding. A principal mechanism in glucocorticoid sensitive cells studied in tissue culture is a new type of translational control of the messenger RNA for the PG synthase enzyme. In common with other examples of translational control this may involve interaction of glucocorticoid-induced or glucocorticoid-activated proteins with a highly conserved 3' untranslated region in the PG synthase mRNA, converting it into a non-translated cryptic form. The glucocorticoid-linked lipocortin/annexin family of proteins may be involved in the process. In many cell types, translation of the cryptic form of PG synthase mRNA is activated by epidermal growth factor (EGF). This is accompanied by phosphorylation of endogenous lipocortin by the tyrosine kinase activity of the EGF receptor. The possibility that glucocorticoids induce specific protein phosphatases needs further exploration. A second mechanism by which glucocorticoids suppress PG synthesis is to inhibit release of arachidonic acid substrate by phospholipase A2 (PLA2). The long-held belief that this is due to a direct inhibitory action of lipocortin on PLA2 has recently been disproved. Instead glucocorticoids may inhibit PLA2 in some cells directly by inducing dephosphorylation of the active form of the enzyme. In vascular muscle cells, glucocorticoids inhibit expression of the PLA2 enzyme both at the transcriptional and translational levels by mechanisms that remain to be determined.