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Cellular and Molecular Life Sciences

, Volume 67, Issue 10, pp 1687–1697 | Cite as

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

  • J. Sandoval
  • J. Pereda
  • J. L. Rodriguez
  • J. Escobar
  • J. Hidalgo
  • L. A. B. Joosten
  • L. Franco
  • J. Sastre
  • G. López-RodasEmail author
Research Article

Abstract

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.

Keywords

Acute necrotic pancreatitis Chromatin immunoprecipitation ChIP Epigenetic Tumor necrosis factor alpha 

Notes

Acknowledgments

This work was supported by research grants from the Ministerio de Ciencia y Tecnología (BFU2007-63120, CSD2006-49 to G. López-Rodas and SAF2006-06963, SAF2009-09500, CSD2007-00020 to J. Sastre) and from the European Commission FP6 Integrated Project Exogenesis (LSHM-CT-2004-005272 to J.Hidalgo).

Supplementary material

18_2010_272_MOESM1_ESM.tif (909 kb)
Suplementary Figure S1. Effect of pentoxyfilline in tnf-α expression and in transcriptional factor recruitment in tnf-α promoter. (A) Quantitative RT-PCR analysis of tnf-α gene expression. β-Actin gene was used as negative control of taurocholate-induced expression. (B) ChIP assay of tnf-α promoter transcriptional factor occupation. α-Actin gene was used as a negative control of the ChIP assay. (C) ImageJ analysis of PCR signals. P: pentoxyfilline treatment; T: taurocholate treatment; P+T: pentoxyfilline plus taurocholate treatment. The statistical significance is indicated as follows: **P < 0.01 vs. control or time 0; ##P < 0.01 vs. taurocholate (TIFF 909 kb)

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Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • J. Sandoval
    • 1
  • J. Pereda
    • 2
  • J. L. Rodriguez
    • 1
  • J. Escobar
    • 2
  • J. Hidalgo
    • 3
  • L. A. B. Joosten
    • 4
    • 5
  • L. Franco
    • 1
  • J. Sastre
    • 2
  • G. López-Rodas
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular BiologyUniversity of ValenciaValenciaSpain
  2. 2.Department of Physiology, School of PharmacyUniversity of ValenciaValenciaSpain
  3. 3.Department of PhysiologyAutonomous University of BarcelonaBarcelonaSpain
  4. 4.Department of MedicineRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  5. 5.Rheumatology Research and Advanced TherapeuticsRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

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