Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells.
The synthesis of interferon-beta (IFNbeta) and IFN-inducible factors elicited by lipopolysaccharide (LPS) depends on the transcriptional activity of interferon regulatory factor 3 (IRF-3) downstream of Toll-like receptor-4 (TLR4). To examine the ability of human newborns to mount TLR4-mediated IRF-3-dependent responses, we analyzed the pattern of genes expressed on the addition ... of LPS to cord blood or cord blood monocyte-derived dendritic cells (moDCs). Expression of IFNbeta and IFN-inducible genes was selectively impaired in neonatal blood and moDCs as compared with their adult counterparts. This selective defect was confirmed by microarray experiments on moDCs. Altered expression of IFN-inducible genes was related to impaired IFNbeta synthesis because IFNbeta signaling was functional in neonatal moDCs. However, addition of exogenous IFNbeta failed to restore LPS-induced IL-12p70 synthesis which was previously shown to be defective in neonatal moDCs. Although LPS-induced IRF-3 nuclear translocation was observed both in adult and neonatal moDCs, IRF-3 DNA-binding activity and association with the coactivator CREB-binding protein (CBP) were decreased in neonatal as compared with adult moDCs. We conclude that impaired IRF-3/CBP interaction in neonatal blood cells exposed to LPS is associated with impaired expression of IFNbeta and IFN-inducible genes. Because IRF-3 activity is also required for IL-12p70 synthesis, our findings provide a molecular basis for the decreased ability of LPS-stimulated neonatal moDCs to elicit Th1-type responses.
Mesh Terms:
Active Transport, Cell Nucleus, Adult, CREB-Binding Protein, Fetal Blood, Gene Expression, Humans, Infant, Newborn, Interferon Regulatory Factor-3, Interferon-beta, Lipopolysaccharides, RNA, Messenger
Active Transport, Cell Nucleus, Adult, CREB-Binding Protein, Fetal Blood, Gene Expression, Humans, Infant, Newborn, Interferon Regulatory Factor-3, Interferon-beta, Lipopolysaccharides, RNA, Messenger
Blood
Date: Apr. 01, 2007
PubMed ID: 17138826
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