Pentoxifylline Prevents Loss of PP2A Phosphatase Activity and Recruitment of Histone Acetyltransferases to Proinflammatory Genes in Acute Pancreatitis

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 ␣ 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-␣) 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-␣) responsive genes and recruitment of transcription factors (nuclear factor B and C/EBP␤) 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.

Ibudilast, a Pharmacologic Phosphodiesterase Inhibitor, Prevents Human Immunodeficiency Virus-1 Tat-Mediated Activation of Microglial Cells

“…PDE inhibitors have been shown to modulate protein phosphatase activity [64], [65], and the involvement of protein phosphatases in the inhibition of Tat-induced TNFα production has been well characterized [61]. Thus, we predicted that the inhibitory actions of ibudilast on TNFα production could be regulated by protein phosphatase activation.…”

Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-α inhibition

“…The antioxidant effect of PTX (Haddad et al 2002) might be involved in PTX in vitro protective effect from TNF-α impairment of ACh-induced relaxation and NO generation. The improvement in sensitivity to endothelial-independent relaxant SNP could be related to the phosphodiesteraseinhibiting activity of PTX (Sandoval et al 2009). In conclusion, PTX protects from vascular contractility impairment in insulin resistance by a mechanism involving TNF-α inhibition and consequently inhibition in leukocyte infiltration and endothelial-cell pyknosis.…”

Tumor Suppressor Lzap Suppresses Wnt/β-Catenin Signaling to Promote Zebrafish Embryonic Ventral Cell Fates via the Suppression of Inhibitory Phosphorylation of Glycogen Synthase Kinase 3

“…In brief, 1 g of protein extracts of sphere-stage embryos were used for each of protein phosphatases (PP) PP2A, PP2B, and PP2C activity assays. Embryos were homogenized in the buffers specific for PP2A, PP2B, and PP2C (33)(34)(35). After centrifugation, the supernatant was further passed through a Sephadex G-25 resin column to remove free phosphates.…”