Effect of Hydrogen Sulfide on the Phosphatidylinositol 3-Kinase-Protein Kinase B Pathway and on Caerulein-Induced Cytokine Production in Isolated Mouse Pancreatic Acinar Cells

We have shown earlier that mouse pancreatic acinar cells produce hydrogen sulfide (H2S) and play a role in the pathogenesis of acute pancreatitis. It is noteworthy that recent evidence indicates that H2S has anti-inflammatory effects. To date, the mechanism by which H2S directly reduces inflammation has not been elucidated. In the present study, we hypothesized that H2S inhibits the production of proinflammatory cytokines by activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Pancreatic acinar cells were treated with the H2S donor, sodium hydrogen sulfide (NaHS) (5, 10, and 30 mu M). To better understand the effect of H2S in inflammation, pancreatic acinar cells were stimulated with caerulein after the addition of NaHS (5, 10, and 30 mu M). We observed that H2S at the 5 mu M concentration down-regulates the activation of NF-kappa B and degradation of I kappa B alpha. However, H2S (5 mu M) activates PI3K as reflected by AKT phosphorylation. We found that H2S-mediated activation of PI3K in caerulein-treated acinar cells correlated with the down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas phosphorylation of p38 and c-Jun NH2-terminal kinase and mitogen-activated protein kinases was unchanged. The PI3K inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] abolished the H2S-mediated activation of AKT and increases tumor necrosis factor alpha and interleukin 1 beta levels in caerulein-treated acinar cells. These findings indicate that the phosphatidylinositol 3-kinase plays a negative role in NaHS-treated pancreatic acinar cells and suggest a role for H2S in the PI3K/AKT pathway in acute pancreatitis.