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.