SUPPRESSION OF PROSTAGLANDIN-H SYNTHASE-2 INDUCTION IN HUMAN MONOCYTES BY IN-VITRO OR IN-VIVO ADMINISTRATION OF INTERLEUKIN-4

IL-4 is a potent modulator of monocyte function, Our previous studies demonstrated that the suppression of monocyte matrix metalloproteinase production by IL-4 is a result of its inhibition of PGE(2) synthesis, which was attributed to an effect on prostaglandin synthase. Here we report on the in vitro and in vivo effects of IL-4 on monocyte prostag landin H synthase-2 (PGHS-2) and its regulation by second messengers. Stimulation of monocytes with either LPS or Con A resulted in the indu ction of PGHS-2 which was significantly inhibited by IL-4, Inhibition of PGHS-2 mRNA and protein was detected at 0.05 to 0.1 ng/ml of IL-4 w ith substantial suppression at 10 to 20 ng/ml. If added later than 2 h r after LPS, IL-4 failed to suppress PGHS-2, indicating that IL-4 acte d early in the signaling cascade, Moreover, the ability of exogenously added PGE(2) or Bt(2)cAMP to restore PGHS-2 production in IL-4-treate d monocytes further suggested early disruption of the pathway, The ear ly event inhibited by IL-4 did not involve suppression of phospholipas e activity, because LPS-induced arachidonic acid release was relativel y unaffected by IL-4. Unlike PGHS-2, PGHS-1, the constitutively expres sed PGHS, was not modulated by IL-4. Thus, IL-4 appears to selectively block PGHS-2 synthesis, thereby blocking subsequent steps in the path way leading to the production of matrix metalloproteinases, In an exte nsion of these findings, we examined peripheral blood monocytes from c ancer patients undergoing IL-4 therapy, In these cells the induction o f PGHS-2 expression by LPS was significantly reduced compared to that of monocytes obtained prior to IL-4 therapy, Although perhaps not rele vant as an antitumor mechanism, these findings have important implicat ions in defining the potent anti-inflammatory activities of IL-4 in vi tro and in vivo. (C) 1996 Academic Press, Inc.