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NF-{kappa}B is required for STAT-4 expression during dendritic cell maturation.

Abstract : 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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-00161345
Contributor : Bérengère Hugot <>
Submitted on : Tuesday, July 10, 2007 - 3:08:08 PM
Last modification on : Monday, January 13, 2020 - 5:08:09 PM

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Sandra Pellegrini, M.E. Remoli, Josiane Ragimbeau, E. Giacomini, V. Gafa, et al.. NF-{kappa}B is required for STAT-4 expression during dendritic cell maturation.. Journal of Leukocyte Biology, Society for Leukocyte Biology, 2007, 81(1), pp.355-63. ⟨10.1189/jlb.0506319⟩. ⟨pasteur-00161345⟩

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