Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells
Autor: | Valentina Albarani, Fabienne Willems, Jean-Louis Ruelle, Jean-Francois Laes, Stanislas Goriely, Dominique De Wit, Muriel Nguyen, Michel Goldman, Ezra Aksoy |
---|---|
Rok vydání: | 2006 |
Předmět: |
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 |
Zdroj: | Blood. 109:2887-2893 |
ISSN: | 1528-0020 0006-4971 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |