During
acute pancreatitis,
protease-activated receptor 2 (PAR2) can be activated by interstitially released
trypsin. In the mild form of
pancreatitis, PAR2 activation exerts local protection against intrapancreatic damage, whereas, in the severe form of
pancreatitis, PAR2 activation mediates some systemic complications. This study aimed to identify the molecular mechanisms of PAR2-mediated protective effects against intrapancreatic damage. A mild form of
acute pancreatitis was induced by an
intraperitoneal injection of
caerulein (40 microg/kg) in rats. Effects of PAR2 activation on intrapancreatic damage and on
mitogen-activated
protein (MAP)
kinase signaling were assessed.
Caerulein treatment activated
extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal
kinase (JNK) within 15 min and maintained phosphorylation of ERK and JNK for 2 h in the rat pancreas. Although PAR2 activation by the pretreatment with
PAR2-activating peptide (AP) itself increased ERK phosphorylation in rat pancreas, the same treatment remarkably decreased
caerulein-induced activation of ERK and JNK principally by accelerating their dephosphorylation. Inhibition of ERK and JNK phosphorylation by the pretreatment with
MAP/ERK kinase (
MEK) or JNK inhibitors decreased
caerulein-induced pancreatic damage that was similar to the effect induced by PAR2-AP. Notably, in
caerulein-treated rats, PAR2-AP cotreatment highly increased the expression of a group of MAP
kinase phosphatases (MKPs) that deactivate ERK and JNK. The above results imply that downregulation of MAP
kinase signaling by MKP induction is a key mechanism involved in the protective effects of PAR2 activation on
caerulein-induced intrapancreatic damage.