Regulation of prostaglandin production in intact fetal membranes by interleukin-1 and its receptor antagonist.
There is strong evidence for the involvement of inflammatory mediators such as interleukin (IL)-1 in the biochemical mechanisms of parturition. Therefore the effects of the IL-1 family (IL-1alpha (1 ng/ml), IL-1beta (1 ng/ml) and the IL-1 receptor antagonist (IL-1ra) (10 ng/ml)) on the regulation of prostaglandin synthesis in term human fetal membranes were investigated. It was found that, after 4 h of culture, IL-1beta increased prostaglandin E2 (PGE2) output approximately twofold. This was associated with both a significant increase in cyclo-oxygenase-2 (COX-2) mRNA levels (approximately fourfold compared with control) and translocation of cytoplasmic phospholipase A2 (cPLA2) from the cytosol to the membrane fraction. IL-1alpha was less effective than IL-1beta at stimulating PGE2 production through similar mechanisms. IL-1ra had no effect on PGE2 output. However, in combination treatments, IL-1ra did not inhibit IL-1alpha- or IL-1beta-stimulated PGE2 output, and increased PGE2 production further compared with IL-1beta alone. IL-1ra decreased IL-1beta-induced COX-2 mRNA expression by about half and significantly increased cPLA2 protein levels, as detected by immunoblotting, when used alone and together with IL-1beta. These results suggest that IL-1ra has partial agonist properties when used together with IL-1alpha and IL-1beta in fetal membranes by increasing cPLA2 protein levels, which leads to an increase in the production of prostaglandins.
Brown
N L
NL
Department of Maternal and Fetal Medicine, Division of Paediatrics, Obstetrics and Gynaecology, Imperial College School of Medicine, Queen Charlotte's and Chelsea Hospital, Goldhawk Road, London W6 0XG, UK.
Alvi
S A
SA
Elder
M G
MG
Bennett
P R
PR
Sullivan
M H
MH
D000704:Analysis of Variance; D046508:Culture Techniques; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000201:enzymology; D015232:Dinoprostone / Q000096:biosynthesis*; D005321:Extraembryonic Membranes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics; D008565:Membrane Proteins; D010741:Phospholipases A; D054467:Phospholipases A2; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D020033:Protein Isoforms / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000494:pharmacology*; D013268:Stimulation, Chemical
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone