Histone methylation is regarded as a stable modification important in the epigenetic regulation of gene expression. Transcriptionally active chromatin is methylated at H3-K4 whereas repressed chromatin is methylated at H3-K9. To investigate the role of histone methylation in an acute inflammatory response, A549 cells were treated with IL-1β and/or the methylase inhibitor 5-azacytidine (5-aza), and histone H3-K4 methylation levels and transcription of secretory leukocyte protease inhibitor (SLPI) were measured. IL-1β stimulation enhanced histone H3-K4 tri-methylation across the SLPI coding region at 24 h. In parallel, IL-1β enhanced recruitment of RNA polymerase II to the SLPI gene. 5-aza attenuated both H3-K4 tri-methylation and RNA polyrnerase II recruitment to a similar extent resulting in reduced SLPI mRNA and protein levels. These data suggest that in addition to epigenetic regulation of constitutive SLPI expression, H3-K4 tri-methylation may play a role in stimulated SLPI expression by modulating RNA polymerase II recruitment and subsequent gene transcription. © 2005 Elsevier Inc. All rights reserved.