title: Substance P treatment stimulates chemokine synthesis in pancreatic acinar cells via the activation of NF-kappaB.
abstract: Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction and to the subsequent systemic inflammatory response, which may result in multiple organ dysfunction and death. Inflammatory mediators, including chemokines and substance P (SP), are known to play a crucial role in the pathogenesis of acute pancreatitis. It has been shown that pancreatic acinar cells produce the chemokine monocyte chemoattractant protein-1 (MCP-1) in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Similarly, SP levels in the pancreas and pancreatic acinar cell expression of neurokinin-1 receptor, the primary receptor for SP, are both increased during secretagogue-induced experimental pancreatitis. This study aims to examine the functional consequences of exposing mouse pancreatic acinar cells to SP and to determine whether it leads to proinflammatory signaling, such as production of chemokines. Exposure of mouse pancreatic acini to SP significantly increased synthesis of MCP-1, macrophage inflammatory protein-1alpha (MIP-1alpha), as well as MIP-2. Furthermore, SP also increased NF-kappaB activation. The stimulatory effect of SP was specific to chemokine synthesis through the NF-kappaB pathway, since the increase in chemokine production was completely attenuated when pancreatic acini were pretreated with the selective NF-kappaB inhibitor NF-kappaB essential modulator-binding domain peptide. This study shows that SP-induced chemokine synthesis in mouse pancreatic acinar cells is NF-kappaB dependent.
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore.
authors.forename: Raina Devi
authors.initials: RD
authors.lastname: Ramnath
authors.forename: Madhav
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000008:administration & dosage*
chemical_list: D018925:Chemokines; D016328:NF-kappa B; D013373:Substance P