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Pentoxifylline Prevents Loss of PP2A Phosphatase Activity and Recruitment of Histone Acetyltransferases to Proinflammatory Genes in Acute Pancreatitis
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 331:609-617
- Publication Year :
- 2009
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2009.
-
Abstract
- Mitogen-activated protein kinases (MAPKs) are considered major signal transducers early during the development of acute pancreatitis. Pentoxifylline is a phosphodiesterase inhibitor with marked anti-inflammatory properties through blockade of extracellular signal regulated kinase (ERK) phosphorylation and tumor necrosis factor alpha production. Our aim was to elucidate the mechanism of action of pentoxifylline as an anti-inflammatory agent in acute pancreatitis. Necrotizing pancreatitis induced by taurocholate in rats and taurocholate-treated AR42J acinar cells were studied. Phosphorylation of ERK and ERK kinase (MEK1/2), as well as PP2A, PP2B, and PP2C serine/threonine phosphatase activities, up-regulation of proinflammatory genes (by reverse transcription-polymerase chain reaction and chromatin immunoprecipitation), and recruitment of transcription factors and histone acetyltransferases/deacetylases to promoters of proinflammatory genes (egr-1, atf-3, inos, icam, il-6, and tnf-alpha) were determined in the pancreas during pancreatitis. Pentoxifylline did not reduce MEK1/2 phosphorylation but prevented the marked loss of serine/threonine phosphatase PP2A activity induced by taurocholate in vivo without affecting PP2B and PP2C activities. The rapid loss in PP2A activity induced by taurocholate in acinar cells was due to a decrease in cAMP levels that was prevented by pentoxifylline. Pentoxifylline also reduced the induction of early (egr-1, atf-3) responsive genes and abrogated the up-regulation of late (inos, icam, il-6, tnf-alpha) responsive genes and recruitment of transcription factors (nuclear factor kappaB and C/EBPbeta) and histone acetyltransferases to their gene promoters during pancreatitis. In conclusion, the beneficial effects of pentoxifylline--and presumably of other phosphodiesterase inhibitors--in this disease seem to be mediated by abrogating the loss of cAMP levels and PP2A activity as well as chromatin-modifying complexes very early during acute pancreatitis.
- Subjects :
- Male
MAPK/ERK pathway
Chromatin Immunoprecipitation
Phosphodiesterase Inhibitors
Blotting, Western
Phosphatase
Anti-Inflammatory Agents
Pharmacology
Biology
Cell Line
Pentoxifylline
Proinflammatory cytokine
Cyclic AMP
Phosphoprotein Phosphatases
medicine
Animals
Rats, Wistar
Extracellular Signal-Regulated MAP Kinases
Histone Acetyltransferases
Inflammation
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
Protein phosphatase 2
medicine.disease
Cyclic Nucleotide Phosphodiesterases, Type 2
Rats
Enzyme Activation
Pancreatitis
Biochemistry
Acute Disease
RNA
Molecular Medicine
Phosphorylation
Mitogen-Activated Protein Kinases
Chromatin immunoprecipitation
medicine.drug
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 331
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....263b7e87f3f26f7ad16da2fc9f696d07