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World J Gastrointest Pharmacol Ther. Jun 6, 2010; 1(3): 75-80
Published online Jun 6, 2010. doi: 10.4292/wjgpt.v1.i3.75
Protein phosphatases and chromatin modifying complexes in the inflammatory cascade in acute pancreatitis
Javier Escobar, Javier Pereda, Alessandro Arduini, Juan Sandoval, Luis Sabater, Luis Aparisi, Gerardo López-Rodas, Juan Sastre
Javier Escobar, Javier Pereda, Alessandro Arduini, Juan Sastre, Department of Physiology, University of Valencia, 46100 Burjasot (Valencia), Spain
Juan Sandoval, Gerardo López-Rodas, Department of Biochemistry & Molecular Biology, University of Valencia, 46100 Burjasot (Valencia), Spain
Luis Sabater, Department of Surgery, University Clinic Hospital, 46010 Valencia, Spain
Luis Aparisi, Laboratory of Pancreatic Function, University Clinic Hospital, 46010 Valencia, Spain
Author contributions: The item on the pathophysiology of pancreatitis was written by Sastre J, Sabater L and Aparisi L; items on chromatin modifying complexes were written by López-Rodas G, Sandoval J and Sastre J; the item on protein phosphatases was written by Escobar J, Pereda J, Arduini A and Sastre J; the item on potential therapy was written by Sastre J; the figure was designed by Escobar J and Pereda J with the supervision of López-Rodas G and Sastre J.
Supported by Grants SAF2006-06963, SAF2009-09500 and Consolider CSD-2007-00020 to Sastre J; BFU2007-63120 and CSD2006-49 to López-Rodas G
Correspondence to: Juan Sastre, Professor, Department of Physiology, School of Pharmacy, University of Valencia, Avda. Vicente Andrés Estellés s/n, 46100 Burjasot (Valencia), Spain. juan.sastre@uv.es
Telephone: +34-96-3543815 Fax: +34-96-3543395
Received: November 25, 2009
Revised: February 10, 2010
Accepted: February 17, 2010
Published online: June 6, 2010
Abstract

Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory cascade in response to local damage of the pancreas. Amplification of the inflammatory cascade requires up-regulation of pro-inflammatory cytokines and this process is mediated not only by nuclear factor κB but also by chromatin modifying complexes and chromatin remodeling. Among the different families of histone acetyltransferases, the p300/CBP family seems to be particularly associated with the inflammatory process. cAMP activates gene expression via the cAMP-responsive element (CRE) and the transcription factor CRE-binding protein (CREB). CREB can be phosphorylated and activated by different kinases, such as protein kinase A and MAPK, and then it recruits the histone acetyltransferase co-activator CREB-binding protein (CBP) and its homologue p300. The recruitment of CBP/p300 and changes in the level of histone acetylation are required for transcription activation. Transcriptional repression is also a dynamic and essential mechanism of down-regulation of genes for resolution of inflammation, which seems to be mediated mainly by protein phosphatases (PP1, PP2A and MKP1) and histone deacetylases (HDACs). Class II HDACs are key transcriptional regulators whose activities are controlled via phosphorylation-dependent nucleo/cytoplasmic shuttling. PP2A is responsible for dephosphorylation of class II HDACs, triggering nuclear localization and repression of target genes, whereas phosphorylation triggers cytoplasmic localization leading to activation of target genes. The potential benefit from treatment with phosphodiesterase inhibitors and histone deacetylase inhibitors is discussed.

Keywords: Dual specificity protein phosphatases; Acute pancreatitis; Phosphodiesterase inhibitors; Cytokines; Histone acetylation; Pentoxifylline; PP2A; Serine/threonine protein phosphatases