Modifying the chromatin structure and interacting with non-histone proteins,
histone deacetylases (HDAC) are involved in vital cellular processes at
different levels. We here specifically investigated the direct effects of
HDAC5 in macrophage activation in response to bacterial or cytokine stimuli.
Using murine and human macrophage cell lines, we studied the expression
profile and the immunological function of HDAC5 at transcription and protein
level in over-expression as well as RNA interference experiments. Toll-like
receptor-mediated stimulation of murine RAW264.7 cells significantly reduced
HDAC5 mRNA within 7 hrs but presented baseline levels after 24 hrs, a
mechanism that was also found for Interferon-γ treatment. If treated with
lipopolysaccharide, RAW264.7 cells transfected for over-expression only of
full-length but not of mutant HDAC5, significantly elevated secretion of
tumour necrosis factor α and of the monocyte chemotactic protein-1. These
effects were accompanied by increased nuclear factor-κB activity. Accordingly,
knock down of HDAC5-mRNA expression using specific siRNA significantly reduced
the production of these cytokines in RAW264.7 or human U937 cells. Taken
together, our results suggest a strong regulatory function of HDAC5 in the
pro-inflammatory response of macrophages