The main goal of our research is to investigate the role of IL-1? in maternal infection-induced alterations of offspring neuroinflammation. There is significant evidence that maternal infection is a significant risk factor for the pathogenesis of various diseases in the offspring at later life. Our laboratory has found that maternal exposure to lipopolysaccharide (LPS), a major component of Gram-negative bacteria cell wall, attenuated the mRNA expression of cytokines, namely tumor necrosis factor (TNF)-???? interleukin (IL)-1??, and IL-6, and chemokines, namely macrophage inflammatory protein (MIP)-1?? MIP-2, and keratinocyte-derived chemokine (KC) in the offspring brain following LPS stimulation, suggesting that maternal LPS has a significant impact on offspring neuroinflammation. However, the mechanisms by which maternal LPS affects offspring neuroinflammation are largely unknown. IL-?, a pivotal mediator of the host defense response to infection, inflammation, and injury, is known to regulate the expression of many other cytokines and chemokines, modulate hypothalamus-pituitary adrenal axis function, and regulate glial and neuronal differentiation during development. IL?? level in maternal serum, placenta, fetal plasma, and fetal brain has been shown to be increased by maternal LPS, and its level is significantly higher in patients with chorionamnionitis than healthy controls. Furthermore, prenatal treatment with recombinant IL-? induces preterm delivery, and a blockade of IL-1 action through administration of IL-1 receptor antagonist (IL-1ra) is able to avert LPS-induced preterm delivery in experimental animal models. Therefore, we hypothesize that IL-? plays a crucial role in mediating the effects of maternal LPS on offspring neuroinflammation. To test this hypothesis, we will examine if and how maternal administration of recombinant IL- alters the expression of LPS-induced neuroinflammatory mediators in the offspring brain at the mRNA and protein levels using oligonucleotide microarrays and antibody arrays respectively in Specific Aim 1, and investigate if and how maternal administration of recombinant IL-1ra counteracts maternal LPS-induced alterations of offspring neuroinflammatory response by examining LPS-induced expression of neuroinflammatory mediators in the offspring brain at the mRNA and protein levels using oligonucleotide microarrays and antibody arrays respectively in Specific Aim 2. The proposed studies will advance the understanding of how maternal IL-? affects offspring neuroinflammation, molecular mechanisms of maternal LPS-mediated effects on offspring neuroinflammation, and how maternal infection contributes to the pathogenesis of various diseases in the offspring. Our results may also contribute to the finding of new diagnostic or therapeutic targets for mitigating maternal infection-induced defects in the offspring. Additionally, the proposed research project will make a special effort to involve both undergraduate and graduate students, and the undergraduate students involved in the proposed research are anticipated to benefit from the research experience and become more determined to continue their studies in biomedical sciences. PUBLIC HEALTH RELEVANCE: Pregnant women have been reported to experience a variety of infections associated with serious and diverse consequences on the health of the fetus. The proposed studies will advance the understanding of how IL-B affects offspring neuroinflammation, shed light on the molecular mechanisms by which maternal infection affects offspring neuroinflammation, and provide insight into how maternal infection contributes to the pathogenesis of various diseases in the offspring at later life. Our results may also contribute to the finding of new diagnostic or therapeutic targets for mitigating maternal infection-induced defects in the offspring.