MELANOCORTIN-1-RECEPTOR DYSFUNCTION REDUCES THE SEVERITY OF A CERULEIN-INDUCED ACUTE PANCREATITIS

Abstract

Introduction: G-protein coupled Melanocortin-1-receptors (MC1R) are mainly expressed on melanocytes but also on the surface of dendritic cells, granulocytes and monocytes. Main ligand of MC1R is alpha-melanocyte-stimulating-peptide (a-MSH). a-MSH has anti-inflammatory properties a dysfunction of MC1R increases the lethal outcome in mice with an experimentally induced colitis. Here we analyzed the function of MC1R in the course of a cerulein-induced pancreatitis. Materials and Methods: An experimental acute pancreatitis was induced in wild type mice and e/e-mice expressing a truncated MC1R without any biological activity by 7 intraperitoneal cerulein injections (50 μg/kg). Mice were sacrificed, pancreas and lung were either homogenized for protein analysis, or fixed for histology and immunocytochemistry. Pancreatitis severity was determined by histology and measuring serum amylase and pancreas trypsin activity. Systemic damage was assessed by quantification of myeloperoxidase (MPO) activity in lung homogenates. Results: Supramaximal cerulein stimulation induces a significant slower increase in serum-amylase activity in e/e-mice compared to wild type mice. Trypsin activity in pancreas homogenates was not significantly altered in cerulein-treated e/e-mice compared to wild type mice. MPO-activity was increased in cerulein-treated animals compared to untreated mice, but no difference could be seen due to the dysfunction of the MC1R. The investigation of the hematoxylin/eosin stained sections of cerulein-treated WT-mice showed clear signs of pancreatitis with zymogen-granula accumulation and vacuole formation in acinar cells, infiltration of leukocytes and oedematous tissue while cerulein-treated e/e-animals developed only mild signs of acute pancreatitis. Conclusions: In contrast to other experimental inflammatory disease models the dysfunction of MC1R in reduced the severity of a cerulein-induced pancreatitis, whereas the systemic impact was not significantly altered. These data indicate that MC1R respectively a-MSH have pro-inflammatory functions in acute pancreatitis.