Submitted June 21, 2006
Accepted November 22, 2006
Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells
Ezra Aksoy, Valentina Albarani, Muriel Nguyen, Jean-Francois Laes, Jean-Louis Ruelle, Dominique De Wit, Fabienne Willems, Michel Goldman*, and Stanislas Goriely
Institute for Medical Immunology (IMI), Universite Libre de Bruxelles, Charleroi, Belgium
Biovallee, Charleroi, Belgium
Research and Development, GlaxoSmithKline Biologicals, Research and Development, Rixensart, Belgium
* Corresponding author; email: mgoldman{at}ulb.ac.be.
The synthesis of interferon (IFN)
and IFN-inducible factors elicited by lipopolysaccharide (LPS) depends on the transcriptional activity of interferon regulatory factor (IRF)-3 downstream of Toll-like receptor (TLR)4. To examine the ability of human newborns to mount TLR4-mediated IRF-3-dependent responses, we analyzed the pattern of genes expressed upon addition of LPS to cord blood or cord blood monocyte-derived dendritic cells (moDCs). Expression of IFN and IFN-inducible genes was selectively impaired in neonatal blood and moDCs as compared to their adult counterparts. This selective defect was confirmed by microarray experiments on moDCs. Altered expression of IFN-inducible genes was related to impaired IFN synthesis since IFN signaling was functional in neonatal moDCs. However, addition of exogenous IFN failed to restore LPS-induced IL-12p70 synthesis which was previously shown to be defective in neonatal moDCs. Whereas 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 to adult moDCs. We conclude that impaired IRF-3/CBP interaction in neonatal blood cells exposed to LPS is associated with impaired expression of IFN and IFN-inducible genes. Since 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.
