The natural interleukin-1 receptor antagonist in term and preterm parturition.
OBJECTIVE
Interleukin-1 has been implicated in the mechanisms responsible for preterm labor in the setting of infection. The interleukin-1 receptor antagonist is a new member of the interleukin-1 gene family that inhibits the biologic effects of interleukin-1 by blocking its receptors. Reduction of interleukin-1-induced prostaglandin production by intrauterine tissues may have potential value in the treatment of preterm labor associated with infection. The purpose of these studies was (1) to determine interleukin-1 receptor antagonist levels in the amniotic fluid of women with term and preterm labor (with and without infection) and (2) to study the effects of interleukin-1 receptor antagonist on interleukin-1-induced prostaglandin biosynthesis by human amnion and chorion.


METHODS
Amniotic fluid was obtained from women in the midtrimester of pregnancy (n = 20), at term pregnancy (with and without labor, n = 69), and in preterm labor (n = 47). Fluid was cultured for aerobic and anaerobic bacteria and Mycoplasmas. Interleukin-1 alpha, interleukin-1 beta, and interleukin-1 receptor antagonist concentrations were measured by immunoassays previously validated for human amniotic fluid. The effect of interleukin-1 receptor antagonist on interleukin-1-induced prostaglandin production by amnion and chorion was studied with primary cultures. Cells were incubated with interleukin-1 receptor antagonist and interleukin-1 alpha or interleukin-1 beta for 16 hours. Prostaglandin E2 released into the media was assayed by immunoassay.


RESULTS
(1) Interleukin-1 receptor antagonist was present in all amniotic fluid samples; (2) amniotic fluid contains the highest interleukin-1 receptor antagonist concentrations detected in any biologic fluid to date; (3) amniotic fluid interleukin-1 receptor antagonist concentrations were not increased in women with preterm labor and intraamniotic infection in spite of dramatically elevated concentrations of interleukin-1 alpha and interleukin-1 beta in the same fluid (median 22 ng/ml and range 0.16 to 70 for preterm labor with negative amniotic fluid culture vs median 30 ng/ml and range 6 to 70 for preterm labor with positive amniotic fluid culture; p > 0.05); (4) interleukin-1 receptor antagonist reduced interleukin-1 beta-induced prostaglandin E2 production by amnion and chorion in a dose-dependent manner; (5) interleukin-1 receptor antagonist by itself did not stimulate prostaglandin E2 release by amnion and chorion when used in concentrations ranging from 0.1 to 1000 ng/ml.


CONCLUSIONS
(1) Interleukin-1 receptor antagonist is a physiologic component of amniotic fluid; (2) the release of interleukin-1 alpha and interleukin-1 beta into the amniotic fluid in women with preterm labor is not associated with an increase in interleukin-1 receptor antagonist levels in amniotic fluid; (3) interleukin-1 receptor antagonist reduces interleukin-1-induced prostaglandin production by amnion and chorion; (4) exogenous anticytokine agents may be of value in the treatment of preterm labor.
Romero
R
R
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut.
Sepulveda
W
W
Mazor
M
M
Brandt
F
F
Cotton
D B
DB
Dinarello
C A
CA
Mitchell
M D
MD
D000328:Adult; D000650:Amnion / Q000378:metabolism; D000653:Amniotic Fluid / Q000378:metabolism; D002823:Chorion / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D007743:Labor, Obstetric / Q000378:metabolism*; D007752:Obstetric Labor, Premature / Q000378:metabolism*; D011247:Pregnancy; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D015232:Dinoprostone