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Intra-amniotic LPS modulation of TLR signaling in lung and blood monocytes of fetal sheep

Maastricht University Medical Center, and GROW Research Institute, University of Maastricht, Maastricht, The Netherlands, b.kramer{at}mumc.nl, University Children's Hospital Würzburg, Würzburg, Germany

Suhas G. Kallapur

Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

Timothy J. Moss

School of Women's and Infants' Health, University of Western Australia, Crowley, Western Australia, Australia

Ilias Nitsos

School of Women's and Infants' Health, University of Western Australia, Crowley, Western Australia, Australia

John P. Newnham

School of Women's and Infants' Health, University of Western Australia, Crowley, Western Australia, Australia

Alan H. Jobe

Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

Epidemiological studies suggest that intra-uterine exposure to inflammation may prime postnatal immune responses. In fetal sheep, intra-amniotic injection of lipopolysaccharide (LPS) induced chorioamnionitis, lung inflammation and maturation, matured lung monocytes to macrophages and initiated systemic tolerance of fetal monocytes to subsequent challenge with LPS. We hypothesized that LPS-mediated chorioamnionitis altered the response of lung and blood monocytes to Toll-like receptor (TLR) ligands such as PamCysK4 (TLR2), flagellin (TLR5), and human CpG-DNA (TLR9). Time-mated ewes were given intra-amniotic injections of LPS or saline. Blood and lung monocytes were assessed after 2 days, 7 days and 2 days and 7 days repetitive LPS injections before delivery at 124 days gestational age (term 150 days). Responsiveness of blood and lung monocytes to TLR-ligands in vitro was assessed by interleukin (IL)-6, tumor necrosis factor- (TNF-) and hydrogen peroxide. Monocytes from preterm controls had minimal responses. Lipopolysaccharide-mediated chorioamnionitis increased IL-6, TNF- and hydrogen peroxide to all TLR agonists in blood and lung monocytes. Repetitive exposure to antenatal LPS reduced IL-6, TNF- and hydrogen peroxide to TLR-ligands suggesting tolerance. Tolerance to TLR-ligands reduced IL-1 receptor associated kinase-4 expression. Thus, repeated fetal exposure to LPS induced tolerance to other TLR-ligands. These modulations of fetal innate immunity have implications for host defense and injury responses in preterm infants.

Key Words: Conditioning • immune tolerance • innate immunity • neonatal sepsis • nosocomial infection

Innate Immunity, Vol. 15, No. 2, 101-107 (2009)
DOI: 10.1177/1753425908100455


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