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 receptormediated manner in pancreatic acinar cells during the pathogenesis of AP.

The ACE2-Angiotensin-(1–7)-Mas Axis Protects Against Pancreatic Cell Damage in Cell Culture

“…It had been shown that angiotensin II can induce redox-regulated ERK1/2 and cAMPresponse element binding protein activation, leading to IL-6 expression in an AT 1 receptor-mediated manner in pancreatic acinar cells during the pathogenesis of AP. 50 Elevated levels of IL-6 and IL-8 have been described in a number of acute conditions such as major surgery, burns, and sepsis. IL-6 and IL-8 may be useful in predicting the progression of SAP.…”

Effects of Local Pancreatic Renin-Angiotensin System on the Microcirculation of Rat with Severe Acute Pancreatitis

“…Key RAS components expression and localization in the acinar and endothelial cells of the exocrine pancreas are found in recent studies. Moreover, these RAS components are responsible to ROS generation responding to chronic hypoxia and acute pancreatitis [ 32 33 34 35 36 ]. For instance, Greenstein et al reported increased plasma RAS activity in patients with acute pancreatitis [ 32 ].…”

Paranode Abnormalities and Oxidative Stress in Optic Nerve Vulnerable to Secondary Degeneration: Modulation by 670 nm Light Treatment

“…H 2 O 2 is produced predominantly from superoxide and continues to be generated in paraformaldehyde fixed tissue [64], indicating that if present, superoxide will be available to react with added DHE in our fixed optic nerve sections. DHE labelling post-fixation has been used to detect increases in superoxide in acute pancreatitis [65].…”