Interferon regulatory factor 3-dependent responses to lipopolysaccharide

The synthesis of interferon (IFN)β 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 IFNβ 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 IFNβ synthesis since 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. Whereas LPSinduced 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 IFNβ 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. only. For personal use at PENN STATE UNIVERSITY on February 23, 2013. bloodjournal.hematologylibrary.org From