Ordered transcriptional factor recruitment and epigenetic regulation of tnf-alpha in necrotizing acute pancreatitis.
Tauhe expression of the critical initiator cytokine TNF-alpha was strongly upregulated in vivo in acute necrotic pancreatitis (AP) in rodents and in vitro in TNF-alpha activated acinar AR42J cells. Upregulation of tnf-alpha, inos, icam-1 and il-6 occurred both in TNF-alpha receptor 1 and 2 knock-out mice, but not in TNF-alpha knock-out mice, in cerulein-induced acute pancreatitis. Chromatin immunoprecipitation analysis showed that transcriptional factors (ELK-1, SP1, NF-kappaB 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-alpha 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-alpha gene regulation will provide deeper understanding of the initiation and development of the inflammatory processes occurring in acute pancreatitis triggered by TNF-alpha cytokine.
Department of Biochemistry and Molecular Biology, University of Valencia, 46100, Valencia, Burjassot, Spain.
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J
Sandoval
J
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Pereda
J L
JL
Rodriguez
J
J
Escobar
J
J
Hidalgo
L A B
LA
Joosten
L
L
Franco
J
J
Sastre
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G
López-Rodas
D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019283:Pancreatitis, Acute Necrotizing / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational; D051381:Rats; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000378:metabolism; D013656:Taurocholic Acid; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D006657:Histones; D018836:Inflammation Mediators; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D013656:Taurocholic Acid