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-niediated development of naive CD4(+) T cells into the Th1 phenotype. Initially thought to he 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-10. 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-kappa B binding site, localized at -969/-959 lip 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-kappa B binding sequence and chromatin immunoprecipitation indicated that p65/p50 and p50/p50 dimers were the main NF-kappa B/Rel proteins involved in STAT-4 gene expression in maturing DC. The mutation of this kappa B site or the overexpression of the repressor IKB alpha 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-kappa B activation and that its induction may be involved in preparing the DC to lie receptive to the cytokine environment present in lymphoid organs.