Critical Paracrine Interactions Between TNF- and IL-10 Regulate Lipopolysaccharide-Stimulated Human Choriodecidual Cytokine and Prostaglandin E 2 Production 1 Timothy A. Sato, 2 Jeffrey A. Keelan, and Murray D. Mitchell Increased production of PGs by gestational membranes is believed to be a principal initiator of term and preterm labor. Intrauterine infection is associated with an inflammatory response in the choriodecidua characterized by elevated production of cytokines and PGs. The precise physiological significance of enhanced choriodecidual cytokine production in the mech- anism of preterm labor remains uncertain. These studies were undertaken to dissect the roles and regulation of endogenous cytokines in regulating PG production by human choriodecidua. We used LPS treatment of human choriodecidual explants as our model system. In choriodecidual explant cultures, LPS (5 g/ml) induced a rapid increase in TNF- production, peaking at 4 h. In contrast, IL-10, IL-1, and PGE 2 production rates peaked 8, 12, and 24 h, respectively, after LPS stimulation. Immunoneutralization studies indicated that TNF- was a primary regulator of IL-1, IL-10, and PGE 2 pro- duction, while IL-1 stimulated only PGE 2 production. Neutralization of endogenous IL-10 resulted in increased TNF- and PGE 2 production. IL-10 treatment markedly decreased TNF- and IL-1 production, but had no effect on PGE 2 production. Taken together, these results demonstrate that the effects of LPS on choriodecidual cytokine and PG production are mod- ulated by both positive and negative feedback loops. In the setting of an infection of the intrauterine, TNF- may be a potential target for treatment intervention; IL-10 could be one such therapeutic. The Journal of Immunology, 2003, 170: 158 –166. P reterm labor resulting in delivery occurs in 5–10% of all pregnancies (1). Despite advances in the understanding of the mechanisms that result in preterm birth, this rate has remained relatively constant for decades. Between 30 and 70% of very preterm births are associated with an ascending intrauterine infection in which microorganisms, originating from the vagina, rise through the choriodecidua and subsequently colonize the cho- rion, amnion, amniotic fluid, and ultimately the fetus (2). In re- sponse to the infective pathogen, the maternal immune system ini- tiates an inflammatory response that frequently results in the onset of preterm labor. The choriodecidua is a tissue composed of interdigitating fetal and maternal cells. In an ascending intrauterine infection it is the first tissue colonized by the microbial pathogen and is the main barrier to progression of the infection into the amniotic cavity. The response of the choriodecidua to the presence of the microorgan- ism is likely an integral part in determining the severity, extent, and consequences of the infection. Human gestational membranes produce a number of proinflam- matory cytokines (e.g., IL-1, TNF-, IL-6, and IL-8) and PGs, both constitutively and in response to inflammatory stimuli and bacterial cell wall products such as LPS (3– 6). At parturition, both at term as well as preterm, there is an increase in the production of these proinflammatory mediators within the uterus, but in the case of intrauterine infection, this response is significantly increased (4, 7, 8). Previous studies have shown that LPS treatment of pregnant mice leads to an increase in IL-1 and PGE 2 production by de- cidual caps in vitro (9, 10) and preterm delivery (3). Mice treated with LPS also have elevated circulating levels of both TNF- and IL-10 (11). These findings indicate that cytokines and PGs pro- duced by gestational tissues as a result of LPS treatment might play an important role in the initiation of preterm labor leading to delivery. In addition to proinflammatory cytokines, gestational tissues can also produce anti-inflammatory cytokines such as IL-10 (12, 13). IL-10 is a potent inhibitor of the production of IL-1, IL-6, IL-8, and TNF- by human monocytes and macrophages (11). It is pro- duced by chorion, decidual, and placental tissues (14 –20) and has been detected in the amniotic fluid of women during late gestation (21–23). IL-10 production by decidual cells in vitro has been re- ported to increase upon treatment with IL-1 and bacterial cell wall products (14 –17). IL-10 inhibits cytokine and PG production by human chorion, decidual, and placental cells in vitro (24 –29), although the effects of endogenous IL-10 on the local inflamma- tory response have not been determined. However, it has been reported that treatment with IL-10 prevented LPS-induced preterm delivery in mice (30) as well as rats (31). IL-10 thus has thera- peutic potential for the treatment of intrauterine infection-associ- ated preterm labor. The present studies were conducted to characterize auto regu- latory interactions between pro- and anti-inflammatory cytokines in choriodecidual explants upon stimulation with LPS. Although it has been established that LPS elicits an inflammatory response within gestational tissues, the significance and role of local medi- ators in the elaboration of the response is not clear. Potential tar- gets for intervention could potentially be identified if they were Liggins Institute and Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand Received for publication August 5, 2002. Accepted for publication October 22, 2002. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This study was supported by the Health Research Council of New Zealand. 2 Address correspondence and reprint requests to Timothy A. Sato, Liggins Institute, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail address: t.sato@auckland.ac.nz The Journal of Immunology Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00