title: Kinetic study of TNF-alpha production and its regulatory mechanisms in acinar cells during acute pancreatitis induced by bile-pancreatic duct obstruction.
abstract: Cytokines play a critical role in acute pancreatitis (AP) but the contribution of different cell sources to cytokine production is unclear. Unfortunately, there are no data concerning the molecular mechanisms involved in the inflammatory response in humans during AP. For this reason, the aim of this study was to analyse the ability of acinar cells, in comparison with leukocytes, to produce TNF-alpha at different stages of AP induced in rats by bile-pancreatic duct obstruction (BPDO) and to investigate the time course of oxidant-sensitive mechanisms involved in cytokine production. The role of oxygen free radicals as messengers of the mechanisms underlying acinar cell TNF-alpha production was assessed in BPDO rats treated with N-acetylcysteine (NAC). While monocytes were not able to produce TNF-alpha until 12 h after inducing AP, acinar cells triggered TNF-alpha production from 6 h after BPDO, at which time the pancreas develops maximal oxidative stress. Phosphorylated p38-MAPK and activated NF-kappaB were detected in acinar cells from 6 h after BPDO. NAC treatment reduced pancreatic glutathione depletion during the early stages of AP and attenuated the activation of p38-MAPK and NF-kappaB for 48 h following BPDO. As a result, acinar cells in NAC-treated rats failed to produce TNF-alpha during AP. In addition, NAC delayed monocyte TNF-alpha production, thereby maintaining low TNF-alpha levels in plasma during BPDO. In conclusion, acinar cells contribute directly to the inflammatory response during BPDO-induced AP by producing TNF-alpha even before inflammatory cells in the peripheral blood. The blockade of oxidant-mediated signal transduction pathways induced by NAC treatment prevented acinar cell TNF-alpha production.
authors.affiliation: Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Ramudo
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Manso
authors.forename: Sara
authors.initials: S
authors.lastname: Sevillano
authors.forename: Isabel
authors.initials: I
authors.lastname: de Dios
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D018929:Cell Culture Techniques; D002779:Cholestasis / Q000150:complications / Q000378:metabolism; D005434:Flow Cytometry; D008297:Male; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism*; D010183:Pancreatic Ducts / Q000378:metabolism; D010195:Pancreatitis / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha