title: Involvement of redox-sensitive extracellular-regulated kinases in angiotensin II-induced interleukin-6 expression in pancreatic acinar cells.
abstract: Angiotensin II has been shown to play a role in the pathogenesis of acute pancreatitis (AP). The present investigation aimed at elucidating redox-sensitive mechanistic pathway involved in proinflammatory actions of angiotensin II during an episode of AP; in particular, the regulation of expression of cytokine interleukin (IL)-6. Exogenous angiotensin II induced IL-6 expression, activation of extracellular-regulated kinase (ERK) 1/2, and superoxide generation in pancreatic acinar cell line AR42J, which were reversed by the angiotensin II type 1 (AT(1)) receptor antagonist, losartan (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-methanol monopotassium salt, C(22)H(23)ClN(6)O). Pharmacological blockade of ERK1/2 improved angiotensin II-induced IL-6 expression. Moreover, angiotensin II-induced ERK1/2 activation was suppressed by antioxidant, indicating that redox-regulated ERK1/2 mediates the cytokine expression. cAMP-responsive element-binding protein (CREB) might be involved in ERK1/2-induced IL-6 expression because phosphorylation of CREB was observed after angiotensin II treatment, which was reversed by losartan and the ERK1/2 inhibitor. These results were in close agreement with the in vivo findings using an obstructive model of AP. Obstruction of the common biliopancreatic duct time-dependently enhanced angiotensinogen levels, which correlated well with superoxide generation, ERK1/2 and CREB phosphorylation, and subsequent IL-6 expression. It is more important that changes in these parameters were antagonized by prophylactic administration of losartan. These in vitro and in vivo results indicate that angiotensin II induces redox-regulated ERK1/2 and CREB activation, thus leading to IL-6 expression in an AT(1) receptor-mediated manner in pancreatic acinar cells during the pathogenesis of AP.
authors.affiliation: Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Yuk Cheung
authors.initials: YC
authors.lastname: Chan
authors.forename: Po Sing
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D019808:Losartan / Q000494:pharmacology; D010084:Oxidation-Reduction; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D019808:Losartan