Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells

被引:74
作者
Aksoy, Ezra
Albarani, Valentina
Nguyen, Muriel
Laes, Jean-Francois
Ruelle, Jean-Louis
De Wit, Dominique
Willems, Fabienne
Goldman, Michel
Goriely, Stanislas
机构
[1] Univ Libre Bruxelles, Inst Med Immunol, B-6041 Gosselies, Belgium
[2] Biovallee, B-6041 Gosselies, Belgium
[3] GlaxoSmithKline Biol, Res & Dev, Rixensart, Belgium
关键词
D O I
10.1182/blood-2006-06-027862
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The synthesis of interferon-beta (IFN beta) 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 IFN beta 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 IFN beta synthesis because IFN beta signaling was functional in neonatal moDCs. However, addition of exogenous IFN beta 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 LIPS is associated with impaired expression of IFN beta 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.
引用
收藏
页码:2887 / 2893
页数:7
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