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NF‐κB is required for STAT‐4 expression during dendritic cell maturation
Author(s) -
Remoli Maria Elena,
Ragimbeau Josiane,
Giacomini Elena,
Gafa Valerie,
Severa Martina,
Lande Roberto,
Pellegrini Sandra,
Coccia Eliana M.
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0506319
Subject(s) - stat4 , stat , biology , transcription factor , microbiology and biotechnology , p50 , chromatin immunoprecipitation , proinflammatory cytokine , cd40 , repressor , dendritic cell , signal transduction , gene expression , promoter , gene , stat3 , immunology , immune system , inflammation , in vitro , genetics , cytotoxic t cell
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‐α and IL‐1β. 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‐κB 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‐κB binding sequence and chromatin immunoprecipitation indicated that p65/p50 and p50/p50 dimers were the main NF‐κB/Rel proteins involved in STAT‐4 gene expression in maturing DC. The mutation of this κB site or the overexpression of the repressor IκBα 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‐κB activation and that its induction may be involved in preparing the DC to be receptive to the cytokine environment present in lymphoid organs.