Influence of progesterone on myometrial contractility in pregnant mice treated with lipopolysaccharide.
OBJECTIVE
To evaluate the effect of progesterone on interleukin (IL)-6, prostaglandin (PG) E2 and nitric oxide (NO) metabolite (NOx) production and contractile activity by NO in pregnant mice treated with lipopolysaccharide (LPS).


METHODS
Pregnant C57BL mice on day 14 of gestation were killed 6 h after i.p. injection of LPS (400 microg/kg) or vehicle. Progesterone (2 mg) was subcutaneously injected 2 h before LPS treatment. Uterine rings were equilibrated in Krebs-Henseleit solution (37 degrees C) bubbled with 20% O2 and 5% CO2 (pH 7.4) for sampling and isometric tension recording. IL-6, PGE2 and NOx productions were measured from the bathing solution. Changes in spontaneous contractile activity in response to cumulative concentrations of l-arginine, diethylamine/nitric oxide (DEA/NO, the NO donor), and 8-bromo-cGMP (8-br-cGMP) were compared. Integral contractile activity over 10 min after each concentration was calculated and expressed as percentage change from basal activity. Statistical analyses were performed using one-way anova followed by Dunnett's test (significance was defined as P < 0.05).


RESULTS
Interleukin-6 (34.7 +/- 6.0 pg/g tissue), PGE2 (66.8 +/- 6.7 pg/g tissue) and NOx (51.0 +/- 5.4 pmol/2 mL/g wet tissue) production were significantly stimulated by LPS treatment (138.2 +/- 23.2, 147.0 +/- 29.0, 98.6 +/- 16.2, respectively; P < 0.05). L-arginine, DEA/NO and 8-br-cGMP concentration-dependently inhibited spontaneous contractions in uterine rings both in LPS-treated and -untreated animals. Treatment with LPS significantly attenuated the maximal inhibition induced by l-arginine, DEA/NO and 8-br-cGMP in uterine rings from pregnant mice. Progesterone significantly decreased the levels of IL-6 production (74.9 +/- 12.1, P < 0.05), but not PGE2 and NOx production, and contractile responses by l-arginine, DEA/NO and 8-br-cGMP.


CONCLUSIONS
The administration of LPS is associated with increases in IL-6, PGE2 and NO, and these increases may or may not have a role to play in LPS-induced preterm labor. Progesterone reduced the LPS-induced increase in IL-6 production and this may be one of the ways that progesterone reduces the risk of preterm labor.
Anbe
Hiroshi
H
Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, Fukushima, Japan.
Okawa
Toshiaki
T
Sugawara
Noboru
N
Takahashi
Hidenori
H
Sato
Akira
A
Vedernikov
Yuri P
YP
Saade
George R
GR
Garfield
Robert E
RE
D000818:Animals; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D042341:Gonadal Hormones / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009215:Myometrium / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects*
D042341:Gonadal Hormones; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D011374:Progesterone; D015232:Dinoprostone