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.
Aksoy
Ezra
E
Institute for Medical Immunology (IMI), Université Libre de Bruxelles, Charleroi, Belgium.
Albarani
Valentina
V
Nguyen
Muriel
M
Laes
Jean-Francois
JF
Ruelle
Jean-Louis
JL
De Wit
Dominique
D
Willems
Fabienne
F
Goldman
Michel
M
Goriely
Stanislas
S
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D050882:CREB-Binding Protein / Q000097:blood; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D050838:Interferon Regulatory Factor-3 / Q000097:blood*; D016899:Interferon-beta / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016899:Interferon-beta; D050882:CREB-Binding Protein; C494363:CREBBP protein, human