PP12 - γ-Glutamyl cysteine modulates the inflammatory response via protein phosphatases

Abstract

Acute pancreatitis (AP) is an acute inflammatory process of the pancreatic gland that may lead to severe systemic complications. Cytokines and oxidative stress play a role in the early pathophysiological events of the disease. Previous studies have shown the antioxidant properties of γ-glutamyl cysteine (γ–GC), a metabolic precursor for the synthesis of glutathione. C57BL/6 mice were treated with cerulein (7 injections each with 50 μg/kg bw). To evaluate the effects of γ-GC, a group of mice with AP was treated with γ-GC (75 mg/kg bw) administered in two doses at 4 and 7 hours after the first cerulein injection. Plasma lipase activity was measured and histological studies were performed to confirm the induction of AP. The aim of this work was to assess the role of γ-GC in the modulation of the inflammatory response and oxidative stress in AP. The activity of pancreatic lipase in plasma increased after induction of acute pancreatitis, but this increase was lower with γ-GC treatment. The histopathological study showed that the inflammatory process and tissue edema were reduced with the γ-GC treatment. The increase in pancreatic myeloperoxydase activity and TNF-α mRNA levels were abrogated in mice treated with γ-GC after AP induction. Moreover, the c-Jun N-terminal kinase (JNK) pathway activation was blocked upon γ-GC treatment. On the contrary, protein levels of protein tyrosine phosphatases SHP-1, SHP-2 and protein serine threonine phosphatase PP2A, which were reduced upon AP induction, were recovered after γ-GC administration. Redox pairs, such as reduced glutathione/oxidized glutathione, and cysteine/cystine were not affected by the γ-GC treatment. In conclusion, our results show the anti-inflammatory properties of the γ-GC in AP, which seem to be mediated by recovering protein phosphatase levels and avoiding the activation of the JNK pathway, independently of the redox thiol status.