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Interleukin-12 (IL-12) is a heterodimeric cytokine produced by macrophages in response to intracellular pathogens. The importance of IL-12 in generation of Th1 response against human pathogens has been characterized. The coactivator p300 is an important histone acetyltransferase (HAT) and has been implicated in the regulation of many genes. Histone deacetylases (HDACs) regulate gene transcription through deacetylation of histones. Whether the reversible histone acetylation/deacetylation modification participates in the regulation of IL-12 p40 transcription expression has not been investigated before. In this study, we analyzed the roles of HDAC1 and p300 in the regulation of human IL-12 p40. Co-transfection studies showed that HDAC1 had a repressing effect on the activity of IL-12 p40 promoter. Contrarily, p300 was able to reinforce the C/EBPβ-mediated activation of IL-12 p40 and it counteracted the HDAC1-mediated repression of the IL-12 promoter. Chromatin immunoprecipitation tests (ChIP) revealed that p300 had a stimulating effect on the acetylation of the histone H3 at IL-12 p40 promoter. In addition, we showed that p300 had a physical interaction with C/EBPβ and can enhance acetylation of C/EBPβ. Data presented in this paper indicate that the reversible histone acetylation/deacetylation modification plays an important role in the transcriptional regulation of IL-12.