Dexamethasone inhibits the induction of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase by phorbol ester in human promonocytic U937 cells

Pro-inflammatory prostaglandins are known to be first catabolized by NAD(+) -dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to inactive meta bolites. This enzyme is under regulatory control by various inflammation-re lated agents. Regulation of this enzyme was investigated in human promonocy tic U937 cells. 15-PGDH activity was found to be optimally induced by phorb ol 12-myristate 13-acetate (PMA) at 10 nM after 24 h of treatment. The indu ction was blocked by staurosporine or CIF 109203X indicating that: the indu ction was mediated by protein kinase C, The induction by PMA was inhibited by the concurrent addition of dexamethasone. Nearly complete inhibition was observed at 50 nM, Other glucocorticoids, such as hydrocortisone and corti costerone, but not sex hormones, were also inhibitory. Inhibition by dexame thasone could be reversed by the concurrent addition of antagonist mifepris tone (RU-486) indicating that the inhibition was a receptor-mediated event. Either induction by PMA or inhibition by dexamethasone the 15-PGDH activit y correlated well with the enzyme protein expression as shown by the Wester n blot analysis. These results provide the first evidence that prostaglandi n catabolism is regulated by glucocorticoids at the therapeutic level. (C) 2000 Elsevier Science B.V. All rights reserved.