The influence of interleukin-1beta on oxytocin signalling in primary cells of human decidua.
OBJECTIVE
Oxytocin (OT) and its corresponding receptor (OTR), synthesized within the pregnant uterus, play a key role in the process of (preterm) labor as part of a paracrine system that regulates symmetrical contractility. In the setting of intrauterine infection, a major cause of preterm labour and birth, decidua serves as a major source of cytokine production. The present study evaluates the time-dependent effect [0-24 h] of the inflammatory cytokine Interleukin-1beta (IL-1beta) treatment on OT signalling and OT stimulated prostaglandin release in primary cultures of human decidua.


METHODS
Primary cultures of human decidua (n=6) were treated with IL-1beta [5 ng/ml] for 0-24h and or indomethacin [100 microM]--an inhibitor of the prostaglandin synthesis--for 0-24 h or for 24 h. OT peptide expression, OTR binding, Inositol triphosphate production (IP(3)), and arachidonic acid (AA) as well as prostaglandin (PGE(2)) release were measured.


RESULTS
IL-1beta transiently reduced cytoplasmic OT peptide at 4-6 h of IL-1beta incubation, while its secretion into the media was increased after 6 h of stimulation. The later was completely blocked by indomethacin. A decrease in OTR mRNA expression and a loss of OTR binding were detected after 8 h and 16 h of IL-1beta treatment, respectively. IL-1beta also decreased IP(3) production and AA release, but significantly enhanced OT mediated PGE(2) production. This effect was completely suppressed by the cyclooxygenase-2 (COX-2) inhibitor NS-398.


CONCLUSIONS
Our data suggest, that IL-1beta indirectly increases OT secretion in primary cultures of human decidua in a time dependent fashion through the production of prostaglandins through COX-2 and that this increase in OT peptide may secondarily down-regulate the OTR and its signalling cascade. These findings might explain the poor effectiveness of oxytocin receptor antagonists as tocolytic agents in the setting of intrauterine infection.
Friebe-Hoffmann
U
U
University of Düsseldorf, Department of Obstetrics and Gynecology, Moorenstr. 5, D-40225 Düsseldorf, Germany. ufriebehoffmann@yahoo.com
Baston
D M
DM
Hoffmann
T K
TK
Chiao
J P
JP
Rauk
P N
PN
D016718:Arachidonic Acid / Q000096:biosynthesis; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D003656:Decidua / Q000187:drug effects* / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000494:pharmacology*; D010121:Oxytocin / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D017931:DNA Primers; D007295:Inositol Phosphates; D053583:Interleukin-1beta; D012333:RNA, Messenger; D018045:Receptors, Oxytocin; D016718:Arachidonic Acid; D010121:Oxytocin; D015232:Dinoprostone; D007213:Indomethacin