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Research Centre for Reproductive Health and Department of Obstetrics and Gynecology, University of Adelaide, Adelaide, Australia
IL-10 is highly expressed in the uterus and placenta and is implicated in controlling inflammation-induced pathologies of pregnancy. To investigate the role of IL-10 in regulating preterm labor, the response of IL-10 null mutant mice to low-dose LPS in late gestation was evaluated. When IL-10 null mutant C57BL/6 (IL-10–/–) and control (IL-10+/+) mice were administered LPS on day 17 of pregnancy, the dose of LPS required to elicit 50% preterm fetal loss was 10-fold lower in IL-10–/– mice than in IL-10+/+ mice. Surviving fetuses in IL-10–/– mice exhibited fetal growth restriction at lower doses of LPS than IL-10+/+ mice. Marked elevation of LPS-induced immunoactive TNF-
and IL-6 was evident in the serum, uterus, and placenta of IL-10–/– mice, and TNF- and IL-6 mRNA expression was elevated in the uterus and placenta, but not the fetus. Serum IL-1, IFN-
, and IL-12p40 were increased and soluble TNFRII was diminished in the absence of IL-10, with these changes also reflected in the gestational tissues. Administration of rIL-10 to IL-10–/– mice attenuated proinflammatory cytokine synthesis and alleviated their increased susceptibility to preterm loss. Exogenous IL-10 also protected IL-10+/+ mice from fetal loss. These data show that IL-10 modulates resistance to inflammatory stimuli by down-regulating proinflammatory cytokines in the uterus and placenta. Abundance of endogenous IL-10 in gestational tissues is therefore identified as a critical determinant of resistance to preterm labor, and IL-10 may provide a useful therapeutic agent in this common condition.
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 project and fellowship grants from the National Health and Medical Research Council (Australia).
2 Address correspondence and reprint requests to Dr. Sarah A. Robertson, Research Centre for Reproductive Health, University of Adelaide, Adelaide, SA 5005 Australia. E-mail address: sarah.robertson{at}adelaide.edu.au
3 Abbreviations used in this paper: m, mouse; gd, gestation day; COX-2, cyclooxygenase-2.
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