1. Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells
- Author
-
Valentina Albarani, Fabienne Willems, Jean-Louis Ruelle, Jean-Francois Laes, Stanislas Goriely, Dominique De Wit, Muriel Nguyen, Michel Goldman, and Ezra Aksoy
- Subjects
Adult ,Lipopolysaccharides ,Lipopolysaccharide ,Microarray ,Immunology ,Active Transport, Cell Nucleus ,Gene Expression ,In Vitro Techniques ,Biology ,Biochemistry ,chemistry.chemical_compound ,Coactivator ,Humans ,RNA, Messenger ,Gene ,Infant, Newborn ,RNA ,Interferon-beta ,Cell Biology ,Hematology ,Fetal Blood ,CREB-Binding Protein ,chemistry ,Cord blood ,TLR4 ,Interferon Regulatory Factor-3 ,Interferon regulatory factors - Abstract
The synthesis of interferon-β (IFNβ) 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 IFNβ 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 IFNβ synthesis because IFNβ signaling was functional in neonatal moDCs. However, addition of exogenous IFNβ 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 IFNβ 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.
- Published
- 2006