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 PGE2 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 prostaglandin H synthase-2 (PGHS-2) and its regulation by second messengers. Stimulation of monocytes with either LPS or Con A resulted in the induction 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 with substantial suppression at 10 to 20 ng/ml. If added later than 2 hr after LPS, IL-4 failed to suppress PGHS-2, indicating that IL-4 acted early in the signaling cascade. Moreover, the ability of exogenously added PGE2 or Bt2cAMP to restore PGHS-2 production in IL-4-treated monocytes further suggested early disruption of the pathway. The early event inhibited by IL-4 did not involve suppression of phospholipase activity, because LPS-induced arachidonic acid release was relatively unaffected by IL-4. Unlike PGHS-2, PGHS-1, the constitutively expressed PGHS, was not modulated by IL-4. Thus, IL-4 appears to selectively block PGHS-2 synthesis, thereby blocking subsequent steps in the pathway leading to the production of matrix metalloproteinases. In an extension of these findings, we examined peripheral blood monocytes from cancer patients undergoing IL-4 therapy. In these cells the induction of PGHS-2 expression by LPS was significantly reduced compared to that of monocytes obtained prior to IL-4 therapy. Although perhaps not relevant as an antitumor mechanism, these findings have important implications in defining the potent anti-inflammatory activities of IL-4 in vitro and in vivo.
Mertz
P M
PM
Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Corcoran
M L
ML
McCluskey
K M
KM
Zhang
Y
Y
Wong
H L
HL
Lotze
M T
MT
DeWitt
D L
DL
Wahl
S M
SM
Wahl
L M
LM
D000595:Amino Acid Sequence; D016718:Arachidonic Acid / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone / Q000494:pharmacology; D004790:Enzyme Induction; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology* / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000187:drug effects; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D015847:Interleukin-4; D016718:Arachidonic Acid; D003994:Bucladesine; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone