Ordered transcriptional factor recruitment and epigenetic regulation of tnf-α in necrotizing acute pancreatitis

Τhe expression of the critical initiator cytokine TNF-α was strongly upregulated in vivo in acute necrotic pancreatitis (AP) in rodents and in vitro in TNF-α activated acinar AR42J cells. Upregulation of tnf-α, inos, icam-1 and il-6 occurred both in TNF-α receptor 1 and 2 knock-out mice, but not in TNF-α knock-out mice, in cerulein-induced acute pancreatitis. Chromatin immunoprecipitation analysis showed that transcriptional factors (ELK-1, SP1, NF-κB and EGR-1) and chromatin modification complexes (HDAC1, HDAC2, GCN5, PCAF and CBP) were recruited and/or released from the promoter in a strictly ordered mechanism. Activation of tnf-α gene was also accompanied by an ordered increased level of histone H3K9, H3K14 and H3K18-acetylation and H3K4 methylation, as well as H4K5 acetylation. A better knowledge of the molecular mechanisms that control tnf-α gene regulation will provide deeper understanding of the initiation and development of the inflammatory processes occurring in acute pancreatitis triggered by TNF-α cytokine. © 2010 Springer Basel AG.