HDAC3, a Class I Histone Deacetylase, Interacts with the P38 Pathway and Suppresses MAPK11-Mediated ATF-2 Activation and TNF Gene Expression.

During inflammatory events, the induction of immediate-early genes, such as tumor necrosis factor α (TNF), is regulated by signaling cascades including the JAK/STAT, NF-kB, and the p38 mitogen-activated protein kinase (MAPK) pathways, which result in phosphorylation-dependent activation of transcription factors. We observed the direct interaction of HDAC3, a class I histone deacetylase, with MAPK11 (p38 beta isoform) by west-western-based screening analysis, pull-down assay and two-hybrid system analysis. Results further indicated that HDAC3 decreases the MAPK11 phosphorylation state and inhibits the activity of the MAPK11-dependent transcription factor ATF-2. LPS-mediated activation of ATF-2 was inhibited by HDAC3 in a time- and dose-dependent manner. Inhibition of HDAC3 expression by RNA interference resulted in increased ATF-2 activation in response to LPS stimulation. In agreement with decreased ATF-2 transcriptional activity by HDAC3, HDAC3 repressed TNF gene expression and TNF protein production observed in response to LPS stimulation. Therefore, our results indicate that HDAC3 interacts directly and selectively with MAPK11, represses ATF-2 transcriptional activity and acts as a regulator of TNF gene expression in LPS stimulated cells, especially in mononuclear phagocytes.