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.

Abstract

We have shown earlier that mouse pancreatic acinar cells produce hydrogen sulfide (H(2)S) and play a role in the pathogenesis of acute pancreatitis. It is noteworthy that recent evidence indicates that H(2)S has anti-inflammatory effects. To date, the mechanism by which H(2)S directly reduces inflammation has not been elucidated. In the present study, we hypothesized that H(2)S 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 H(2)S donor, sodium hydrogen sulfide (NaHS) (5, 10, and 30 microM). To better understand the effect of H(2)S in inflammation, pancreatic acinar cells were stimulated with caerulein after the addition of NaHS (5, 10, and 30 microM). We observed that H(2)S at the 5 microM concentration down-regulates the activation of NF-kappaB and degradation of IkappaB alpha. However, H(2)S (5 microM) activates PI3K as reflected by AKT phosphorylation. We found that H(2)S-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 NH(2)-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 H(2)S-mediated activation of AKT and increases tumor necrosis factor alpha and interleukin 1beta 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 H(2)S in the PI3K/AKT pathway in acute pancreatitis.

• Authors: Ramasamy Tamizhselvi, Jia Sun, Yung-Hua Koh, Madhav Bhatia
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 329 Issue 3 Pg. 1166-77 (Jun 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 19258518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromones
• Cytokines
• Enzyme Inhibitors
• I-kappa B Proteins
• Morpholines
• NF-kappa B
• Nfkbia protein, mouse
• Phosphoinositide-3 Kinase Inhibitors
• NF-KappaB Inhibitor alpha
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Ceruletide
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinases
• Hydrogen Sulfide

Topics

• Animals
• Ceruletide (pharmacology)
• Chromones (pharmacology)
• Cytokines (biosynthesis)
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hydrogen Sulfide (pharmacology)
• I-kappa B Proteins (metabolism)
• Mice
• Mice, Inbred Strains
• Mitogen-Activated Protein Kinases (metabolism)
• Morpholines (pharmacology)
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Pancreas, Exocrine (cytology, drug effects, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)