Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms

Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms

1. Address for reprint requests and other correspondence: C. Schäfer, Dept. of Medicine II, Klinikum Neumarkt, Nürnberger Str. 12, 92318 Neumarkt i. d. Opf., Germany (e-mail: claus.schaefer@klinikum.neumarkt.de).

• Submitted 30 March 2012.
• Accepted 30 October 2012.

Abstract

The endocannabinoid system has been shown to mediate beneficial effects on gastrointestinal inflammation via cannabinoid receptors 1 (CB₁) and 2 (CB₂). These receptors have also been reported to activate the MAP kinases p38 and c-Jun NH₂-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, CB₁−/−, 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 CB₁ and CB₂ are expressed in mouse pancreatic acini. During acute pancreatitis, an upregulation especially of CB₂ on apoptotic cells occurred. The unselective CB₁/CB₂ agonist HU210 ameliorated pancreatitis in wild-type and CB₁−/− mice, indicating that this effect is mediated by CB₂. Furthermore, blockade of CB₂, not CB₁, with selective antagonists engraved pathology. Stimulation with a selective CB₂ 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 CB₂-activated and MAP kinase-dependent pathway that modulates cytokine expression and reduces pancreatic injury and affiliated complications.