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... 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. cannabinoids CB 2 p38 MK2 experimental pancreatitis Copyright © 2013 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print November 8, 2012 , doi: 10.​1152/​ajpgi.​00133.​2012 AJP - GI January 15, 2013 vol. 304 no. 2 G181-G192 » Abstract Full Text Full Text (PDF) All Versions of this Article: ajpgi.00133.2012v1 304/2/G181 most recent Classifications Pancreas Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Michler, T. Articles by Schäfer, C. PubMed PubMed citation Articles by Michler, T. Articles by Schäfer, C. Related Content Load related web page information Current Content January 15, 2013 Alert me to new issues of AJP - GI About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2013 the American Physiological Society Print ISSN: 0193-1857 Online ISSN: 1522-1547 var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-2924550-1"); pageTracker._trackPageview(); } catch(err) {} var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-189672-30"); pageTracker._setDomainName(".physiology.org"); pageTracker._trackPageview(); } catch(err) {} http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Gastrointestinal and Liver Physiology The American Physiological Society

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

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Publisher
The American Physiological Society
Copyright
Copyright © 2013 the American Physiological Society
ISSN
0193-1857
eISSN
1522-1547
DOI
10.1152/ajpgi.00133.2012
Publisher site
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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. cannabinoids CB 2 p38 MK2 experimental pancreatitis Copyright © 2013 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print November 8, 2012 , doi: 10.​1152/​ajpgi.​00133.​2012 AJP - GI January 15, 2013 vol. 304 no. 2 G181-G192 » Abstract Full Text Full Text (PDF) All Versions of this Article: ajpgi.00133.2012v1 304/2/G181 most recent Classifications Pancreas Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Michler, T. Articles by Schäfer, C. PubMed PubMed citation Articles by Michler, T. Articles by Schäfer, C. Related Content Load related web page information Current Content January 15, 2013 Alert me to new issues of AJP - GI About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2013 the American Physiological Society Print ISSN: 0193-1857 Online ISSN: 1522-1547 var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-2924550-1"); pageTracker._trackPageview(); } catch(err) {} var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-189672-30"); pageTracker._setDomainName(".physiology.org"); pageTracker._trackPageview(); } catch(err) {}

Journal

AJP - Gastrointestinal and Liver PhysiologyThe American Physiological Society

Published: Jan 15, 2013

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