Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain

Department of Obstetrics and Gynecology, Harbor-University of California Los Angeles Medical Center and Research and Education Institute, Torrance, California 90502 Submitted 18 November 2003 ; accepted in final form 19 February 2004 Perinatal infections are a risk factor for fetal neurological pathologies, including cerebral palsy and schizophrenia. Cytokines that are produced as part of the inflammatory response are proposed to partially mediate the neurological injury. This study investigated the effects of intraperitoneal injections of lipopolysaccharide (LPS) to pregnant rats on the production of cytokines and stress markers in the fetal environment. Gestation day 18 pregnant rats were treated with LPS (100 µg/kg body wt ip), and maternal serum, amniotic fluid, placenta, chorioamnion, and fetal brain were harvested at 1, 6, 12, and 24 h posttreatment to assay for LPS-induced changes in cytokine protein (ELISA) and mRNA (real-time RT-PCR) levels. We observed induction of proinflammatory cytokines interleukin (IL)-1 , IL-6, and tumor necrosis factor- (TNF- ) as well as the anti-inflammatory cytokine IL-10 in the maternal serum within 6 h of LPS exposure. Similarly, proinflammatory cytokines were induced in the amniotic fluid in response to LPS; however, no significant induction of IL-10 was observed in the amniotic fluid. LPS-induced mRNA changes included upregulation of the stress-related peptide corticotropin-releasing factor in the fetal whole brain, TNF- , IL-6, and IL-10 in the chorioamnion, and TNF- , IL-1 , and IL-6 in the placenta. These findings suggest that maternal infections may lead to an unbalanced inflammatory reaction in the fetal environment that activates the fetal stress axis. endotoxin; tumor necrosis factor; interleukin; brain; cerebral palsy; chorioamnionitis Address for reprint requests and other correspondence: D. A. Gayle, Dept. of Obstetrics and Gynecology, Harbor-UCLA Medical Center and Research and Education Institute, RB-1, Box 446, Torrance, CA 90502 (E-mail: dgayle{at}ucla.edu ).