PKC δ mediates pro-inflammatory responses in a mouse model of caerulein-induced acute pancreatitis.
Acute pancreatitis is an inflammatory disorder of the pancreas. Protein kinase C (PKC) δ plays an important role in mediating chemokine production in mouse pancreatic acinar cells. This study aims to investigate the role of PKC δ in the pathogenesis of acute pancreatitis and to explore the mechanisms through which PKC δ mediates pro-inflammatory signaling. Acute pancreatitis was induced in mice by ten hourly intraperitoneal injections of caerulein. PKC δ translocation inhibitor peptide (δV1-1) at a dose of 1.0 mg/kg or Tat (carrier peptide) at a dose of 1.0 mg/kg was administered to mice either 1 h before or 1 h after the first caerulein injection. One hour after the last caerulein injection, the mice were killed and pancreas, lungs, and blood were collected. Prophylactic and therapeutic treatment with δV1-1 attenuated caerulein-induced plasma amylase levels and pancreatic edema. Treatment with δV1-1 decreased myeloperoxidase activity and monocyte chemotactic protein-1 levels in both pancreas and plasma. PKC δ mediated acute pancreatitis by activating pancreatic nuclear factor κB, activator protein-1, and mitogen-activated protein kinases. Moreover, blockade of PKC δ attenuated lung myeloperoxidase activity and edema. Histological examination of pancreatic and lung sections confirmed protection against acute pancreatitis. Treatment with Tat had no protective effect on acute pancreatitis. Blockade of PKC δ represents a promising prophylactic and/or therapeutic tool for the treatment of acute pancreatitis.
Ramnath
Raina Devi
RD
Department of Pharmacology, National University of Singapore, Singapore, 117456, Singapore.
Sun
Jia
J
Bhatia
Madhav
M
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002108:Ceruletide / Q000494:pharmacology*; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007053:Ice; D007249:Inflammation / Q000378:metabolism*; D055370:Lung Injury / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000150:complications / Q000276:immunology* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D018925:Chemokines; D007053:Ice; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D002108:Ceruletide; D009195:Peroxidase; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; D000681:Amylases