Pancreatitis activates pancreatic apelin-APJ axis in mice

Abstract

Pancreatitis is classified into acute pancreatitis (AP) and chronic pancreatitis (CP). Apelin, a small regulatory peptide, is the endogenous ligand for the APJ receptor. Apelin and APJ are expressed in the pancreas. The aims of this study were to examine whether apelin influences the inflammatory and fibrosis responses to pancreatitis in mice and to identify mechanisms behind apelin's activities. Supramaximal cerulein induction of AP or CP caused significant ( P < 0.05) elevations in pancreatic apelin and APJ expression. Levels declined during the recovery phases. In apelin gene-knockout mice with pancreatitis, pancreatic neutrophil invasion and myeloperoxidase activity were enhanced significantly, and apelin treatment suppressed both. Apelin exposure reduced CP-induced elevations of extracellular matrix-associated proteins. Apelin inhibited PDGF-simulated connective tissue growth factor production and proliferation of pancreatic stellate cells (PSCs). Serum granulocyte colony-stimulating factor and keratinocyte cytokine levels were higher in apelin gene-knockout than wild-type mice with pancreatitis. Apelin reduced AP- and CP-induced elevations in pancreatic NF-κB activation. Together, these findings imply that the pancreatic apelin-APJ system functions to curb the inflammatory and fibrosis responses during pancreatitis. Furthermore, findings suggest that apelin reduces inflammation and fibrosis by reducing neutrophil recruitment and PSC activity. Inhibition of neutrophil invasion may be mediated by reduced keratinocyte cytokine and granulocyte colony-stimulating factor secretion. Apelin-induced reductions in PSC proliferation and connective tissue growth factor production are putative mechanisms underlying apelin's inhibition of extracellular matrix production. The apelin-associated changes in NF-κB binding may be linked to apelin's regulation of pancreatic inflammatory and fibrosis responses during pancreatitis.

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

“…This pancreatic network among BMP2, apelin, and PTHrP reinforces the complex and interactive nature of endogenous protective and injurious signals evoked by CP. Based on these findings and earlier work (2,3,11,12,17), the inflammation-fibrosis cascade evoked during pancreatitis may be amenable to pharmacologic interventions in the clinic.…”

“…For PDL-induced CP in adult male mice, the splenic lobe of the pancreas was selectively ligated by a ligature with aide of a surgical microscope (20). CP was also induced in mice by repetitive administration of a cholecystokinin analog, Cer (5 hourly ip injections, 50 g/kg, on Monday, Wednesday, and Friday mornings for 3 consecutive weeks) (17,29,34,42). Mice were killed at selected intervals after PDL or start of Cer injections for harvest of the pancreas.…”

“…Harvested pancreata were then processed for histological examination or extraction of total cellular RNA, total protein, or pancreatic apelin immunoreactivity. Blood was collected at death and prepared by centrifugation for measurement of serum amylase levels by means of the Phadebas Amylase Test (Pharmacia and Upjohn Diagnostics, Uppsala, Sweden) (17). To assess the influence of BMP2 administration on CP-induced upregulation of pancreatic TNF-␣, IL-6, ICAM, and MIP-1␣ expression, CP was induced by repetitive Cer administration for 2 wk in adult male mice.…”

“…The bone morphogenetic protein-2 (BMP2), apelin, and parathyroid hormone-related protein (PTHrP) signaling systems are expressed in the rodent and human pancreas (2,3,12,17). BMP2 is a member of the transforming growth factor-␤ (TGF-␤) superfamily of growth factors.…”

“…The activities of PTHrP are mediated by parathyroid hormone receptor 1 (PTHR1), also a GPCR. Earlier studies from our laboratories demonstrated that BMP2 and apelin suppressed the inflammatory and fibrosis responses of pancreatitis whereas PTHrP signaling promoted pancreatitisassociated inflammation and fibrosis (2,3,11,12,17). In both the repetitive cerulein (Cer-)-induced models of acute pancreatitis (AP) and CP in the mouse, pancreatic BMP2 and apelin expression and PTHrP protein levels are upregulated robustly (3,11,12,17).…”