NF-{kappa}B is required for STAT-4 expression during dendritic cell maturation.
The transcription factor STAT-4 plays a pivotal role in the IL-12-mediated development of naive CD4+ T cells into the Th1 phenotype. Initially thought to be restricted to the lymphoid lineage, STAT-4 was subsequently shown to be expressed in the myeloid compartment, mainly in activated monocytes, macrophages, and dendritic cells (DC). Here, we have studied STAT-4 in human monocyte-derived DC, and we demonstrated that its expression can be induced by multiple stimuli, such as the ligands for TLR-4, TLR-2, and TLR-3, different pathogens, CD40 ligand, and the proinflammatory cytokines TNF-alpha and IL-1beta. It is interesting that we found that STAT-4 is tyrosine-phosphorylated in response to type I IFN but not IL-12 in human mature DC. Cloning and functional analysis of the STAT-4 promoter showed that a NF-kappaB binding site, localized at -969/-959 bp upstream of the transcriptional start site, is involved in the regulation of this gene in primary human DC. EMSAs using a probe containing this NF-kappaB binding sequence and chromatin immunoprecipitation indicated that p65/p50 and p50/p50 dimers were the main NF-kappaB/Rel proteins involved in STAT-4 gene expression in maturing DC. The mutation of this kappaB site or the overexpression of the repressor IkappaBalpha exerted an inhibitory effect on a STAT-4 promoter-driven reporter as well as on STAT-4 expression. Altogether, these results indicate that STAT-4 can be finely tuned along with DC maturation through NF-kappaB activation and that its induction may be involved in preparing the DC to be receptive to the cytokine environment present in lymphoid organs.
Remoli
Maria Elena
ME
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy.
Ragimbeau
Josiane
J
Giacomini
Elena
E
Gafa
Valerie
V
Severa
Martina
M
Lande
Roberto
R
Pellegrini
Sandra
S
Coccia
Eliana M
EM
D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D050797:STAT4 Transcription Factor; D018808:Transcription Factor AP-1