Progestin suppresses thrombin- and interleukin-1beta-induced interleukin-11 production in term decidual cells: implications for preterm delivery.
BACKGROUND
Decidual inflammation and hemorrhage are major contributors to the pathogenesis of preterm delivery (PTD). IL-11 is a cytokine with pleiotropic biological effects, including induction of T helper cell type 2 and inhibition of T helper cell type 1 cytokine responses. Paradoxically, it enhances the synthesis of prostaglandins, which induce labor.


OBJECTIVE
The objectives of this study were to evaluate in vivo IL-11 expression in decidua after term and preterm deliveries and evaluate the effects of the primary mediators of inflammation, IL-1beta and TNF-alpha, as well as the primary regulator of hemostasis, thrombin, on IL-11 expression in cultured term decidual cells (DCs).


METHODS
Human decidua from uncomplicated term deliveries and chorioamnionitis- or placental abruption-related PTDs were immunostained for IL-11. Cultures of DCs were primed with estradiol (E2) or with E2 and medroxyprogesterone acetate (MPA), then incubated in a defined medium with corresponding steroid(s) with or without IL-1beta, TNF-alpha, or thrombin. IL-11 levels in DC-defined media were assessed by ELISA and Western blotting; IL-11 mRNA levels were measured by quantitative RT-PCR.


RESULTS
IL-11 immunostaining was significantly higher in DCs after PTD compared with those after term delivery (P < 0.05). In the absence of cytokines or thrombin, IL-11 levels in the defined medium were 47% lower in incubations with E2 plus MPA vs. E2 alone (P = 0.001). IL-1beta and thrombin elevated IL-11 output during incubations with E2 [24-fold (P < 0.05) and 120-fold (P < 0.05), respectively]. These increases were blunted by the addition of MPA [13-fold (P < 0.05) and 36-fold (P < 0.05), respectively]. Western blot analysis confirmed the ELISA results, and RT-PCR demonstrated corresponding effects on IL-11 mRNA levels. Unexpectedly, TNF-alpha did not affect IL-11 levels.


CONCLUSIONS
Because excess IL-1beta and thrombin generation are associated with chorioamnionitis- and abruption-related PTD, respectively, these findings add to our understanding of the genesis of inflammation- and abruption-associated prematurity.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, FMB 334, P.O. Box 208063, New Haven, Connecticut 06520-8063, USA.
Hakan
H
Cakmak
Frederick
F
Schatz
S-T Joseph
ST
Huang
Lynn
L
Buchwalder
Mizanur
M
Rahman
Aydin
A
Arici
Charles J
CJ
Lockwood
D002478:Cells, Cultured; D003656:Decidua / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004338:Drug Combinations; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D017370:Interleukin-11 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D007743:Labor, Obstetric / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D007752:Obstetric Labor, Premature / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*
D004338:Drug Combinations; D018836:Inflammation Mediators; D007375:Interleukin-1; D017370:Interleukin-11; D012333:RNA, Messenger; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D013917:Thrombin