Intrauterine infection is a common trigger for preterm birth and is also a risk factor for the subsequent development of neurodevelopmental abnormalities in the neonate. Bacterial lipopolysaccharide (LPS) binds to toll-like receptor-4 (TLR-4) to activate proinflammatory signaling pathways, which are implicated in both preterm delivery and antenatal brain injury. The transcription factor nuclear factor-kappaB (NF-kappaB) is a key player in the orchestration of the inflammatory response and has a central role in parturition. Here we show that intrauterine administration of TLR-4-specific LPS to pregnant mice results in the activation of NF-kappaB in the maternal uterus and the fetal brain, up-regulation of proinflammatory proteins cyclooxygenase-2, chemokine ligand 1, ChemoKine (C-C motif) ligand 2, and cytosolic phospholipase A(2) in myometrium, and induction of preterm delivery. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an antiinflammatory prostaglandin that plays a role in promoting the resolution of inflammation. We report that coadministration of 15d-PGJ(2) and LPS to pregnant mice delays LPS-induced preterm delivery and confers protection from LPS-induced fetal mortality. This is associated with inhibition of myometrial NF-kappaB, cytosolic phospholipase A(2), and c-Jun N-terminal kinase activation, and of inflammatory protein synthesis. Therefore 15d-PGJ(2) has anti-inflammatory effects via inhibition of multiple aspects of inflammation-driven TRL-4 signaling pathway. Thus, 15d-PGJ(2) or compounds with similar antiinflammatory functions may have potential as therapeutic agents in the management of preterm labor with the added advantage of preventing detrimental effects to the fetus that may result from infection/inflammation.