Involvement of redox-sensitive extracellular-regulated kinases in angiotensin II-induced interleukin-6 expression in pancreatic acinar cells.
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.
Chan
Yuk Cheung
YC
Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Leung
Po Sing
PS
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
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