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¹ Laboratoire d'Immunologie Expérimentale, Université Libre de Bruxelles, B-1070 Bruxelles et Institut d'Immunologie Médicale, B-6041 Gosselies, Belgium
² Service de Chimie Biologique, Laboratoire de Virologie Moléculaire, Institut de Biologie et Médecine Molécularies, Université Libre de Bruxelles, B-6041 Gosselies, Belgium

Address correspondence to Michel Goldman, Hôpital Erasme, Dept. of Immunology, 808 route de Lennik, B-1070 Brussels, Belgium. Phone: 32-2-555-38-62; Fax: 32-2-555-44-99; email: mgoldman{at}ulb.ac.be

To gain insight into the inability of newborns to mount efficient Th1 responses, we analyzed the molecular basis of defective IL-12(p35) expression in human neonatal monocyte-derived dendritic cells (DCs). Determination of IL-12(p35) pre-mRNA levels by real-time RT-PCR revealed that transcriptional activation of the gene in lipopolysaccharide-stimulated neonatal DCs was strongly impaired compared with adult DCs. We next showed that p50/p65 and p65/p65 dimers interact with kB#1 site, a critical cis-acting element of the IL-12(p35) promoter. We found that LPS-induced p65 activation was similar in adult and newborn DCs. Likewise, in vitro binding activity to the Sp1#1 site, previously shown to be critical for IL-12(p35) gene activation, did not differ in adults and newborns. Since the accessibility to this Sp1#1 site was found to depend on nucleosome remodeling, we used a chromatin accessibility assay to compare remodeling of the relevant nucleosome (nuc-2) in adult and neonatal DCs. We observed that nuc-2 remodeling in neonatal DCs was profoundly impaired in response to lipopolysaccharide. Both nuc-2 remodeling and IL-12(p35) gene transcription were restored upon addition of recombinant interferon-. We conclude that IL-12(p35) transcriptional repression in neonatal DCs takes place at the chromatin level.

Key Words: cord blood • newborn • nucleosome • NF-B • Sp1

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