BATF2 activates DUSP2 gene expression and up-regulates NF-κB activity via phospho-STAT3 dephosphorylation

Growing evidence has revealed that the transcription factor basic leucine zipper transcription factor ATF-like 2 (BATF2) has unique transcriptional activities, including regulating cytokines via TLR signals in macrophages, which affect mortality due to infection and cancer. On the basis of genome-wide analyses using the chromatin immunoprecipitation-sequencing technique, we found that dual-specificity phosphatase 2 (Dusp2) had a significantly lower acetyl-histone status in Batf2(-/-)bone marrow-derived macrophages (BMDMs) compared with wild-type (WT) BMDMs.The phosphatase DUSP2 has been reported to play a critical role in inflammatory responses. Therefore, we evaluated the BATF2 transcriptional activities on the Dusp2 promoter. We found that the DUSP2 and IL-12 p40 expression levels were significantly lower in Batf2(-/-) BMDMs than in WT controls following their stimulation with TLR7 ligands. Further in vitro studies revealed that phospho-STAT3 was up-regulated and NF-kappa B p50/p65 were down-regulated in Batf24(-/-)BMDMs compared with their levels in WT controls. Additionally, T(h)1 immunity was impaired in Batf2(-/-)mice following their stimulation with TLR7 ligands. We also found that BATF2 interacts with NF-kappa B p65 and promotes DUSP2 expression through the NF-kappa B-binding site in the Dusp2 promoter at-203 to-121. Collectively, our findings suggest that BATF2 activates DUSP2 gene expression and up-regulates NF-kappa B activity via phospho-STAT3 dephosphorylation.