title: Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms.
abstract: The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB(1)) and 2 (CB(2)). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH(2)-terminal kinase (JNK), which are involved in early acinar events leading to acute pancreatitis and induction of proinflammatory cytokines. Our aim was to examine the role of cannabinoid receptor activation in an experimental model of acute pancreatitis and the potential involvement of MAP kinases. Cerulein pancreatitis was induced in wild-type, CB(1)-/-, and MK2-/- mice pretreated with selective cannabinoid receptor agonists or antagonists. Severity of pancreatitis was determined by serum amylase and IL-6 levels, intracellular activation of pancreatic trypsinogen, lung myeloperoxidase activity, pancreatic edema, and histological examinations. Pancreatic lysates were investigated by Western blotting using phospho-specific antibodies against p38 and JNK. Quantitative PCR data, Western blotting experiments, and immunohistochemistry clearly show that CB(1) and CB(2) are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB(2) on apoptotic cells occurred. The unselective CB(1)/CB(2) agonist HU210 ameliorated pancreatitis in wild-type and CB(1)-/- mice, indicating that this effect is mediated by CB(2). Furthermore, blockade of CB(2), not CB(1), with selective antagonists engraved pathology. Stimulation with a selective CB(2) agonist attenuated acute pancreatitis and an increased activation of p38 was observed in the acini. With use of MK2-/- mice, it could be demonstrated that this attenuation is dependent on MK2. Hence, using the MK2-/- mouse model we reveal a novel CB(2)-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications.
authors.affiliation: Department of Medicine II, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Michler
authors.forename: Martin
authors.initials: M
authors.lastname: Storr
authors.forename: Johannes
authors.initials: J
authors.lastname: Kramer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ochs
authors.forename: Antje
authors.initials: A
authors.lastname: Malo
authors.forename: Simone
authors.initials: S
authors.lastname: Reu
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Claus
authors.initials: C
authors.lastname: Schäfer
mesh_terms: D000681:Amylases / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002186:Cannabinoids / Q000494:pharmacology*; D002108:Ceruletide; D004195:Disease Models, Animal; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D004789:Enzyme Activation; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000201:enzymology; D010195:Pancreatitis / Q000097:blood / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014362:Trypsinogen / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000681:Amylases; D000893:Anti-Inflammatory Agents; D002186:Cannabinoids; D002108:Ceruletide; D013759:Dronabinol; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D009195:Peroxidase; D017346:Protein Serine-Threonine Kinases; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014362:Trypsinogen; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C571431:Cnr2 protein, mouse; C062018:HU 211; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC