Activation of Cannabinoid Receptor 2 1 reduces inflammation in acute experimental 2 pancreatitis via intra - acinar activation of p 38 3 and MK 2 - dependent mechanisms 4

24 Articles in PresS. Am J Physiol Gastrointest Liver Physiol (November 8, 2012). doi:10.1152/ajpgi.00133.2012 Copyright © 2012 by the American Physiological Society. 2 The endocannabinoid system has been shown to mediate beneficial effects on 25 gastrointestinal inflammation via Cannabinoid receptor 1 (CB1) and 2 (CB2). These 26 receptors have also been reported to activate the MAP-kinases p38 and c-jun n27 terminal kinase (JNK), which are involved in early acinar events leading to acute 28 pancreatitis and induction of pro-inflammatory cytokines. Our aim was to examine the 29 role of cannabinoid receptor activation in an experimental model of acute pancreatitis 30 and the potential involvement of MAP-kinases. Cerulein-pancreatitis was induced in 31 wild-type, CB1-/and MK2-/mice pre-treated with selective cannabinoid receptor 32 agonists or antagonists. Severity of pancreatitis was determined by serum amylase 33 and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung 34 myeloperoxidase activity, pancreatic edema and histological examinations. 35 Pancreatic lysates were investigated by western blotting using phospho-specific 36 antibodies against p38 and JNK. QPCR-data, western blotting experiments and 37 immunohistochemistry clearly show that CB1 and CB2 are expressed in mouse 38 pancreatic acini. During acute pancreatitis, an up-regulation especially of CB2 on 39 apoptotic cells occurred. The unselective CB1/CB2-agonist HU210 ameliorated 40 pancreatitis in wild-type and CB1-/mice, indicating that this effect is mediated by 41 CB2. Furthermore, blockade of CB2, not CB1, with selective antagonists engraved 42 pathology. Stimulation with a selective CB2-agonist attenuated acute pancreatitis and 43 an increased activation of p38 was observed in the acini. Using MK2-/mice, it could 44 be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2-/45 mouse model we reveal a novel CB2-activated and MAP-kinase dependent pathway 46 that modulates cytokine expression and reduces pancreatic injury and affiliated 47 complications. 48