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.
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ABSTRACT: Hydrogen sulfide (H2S) is a well-known toxic gas that is synthesized in the human body from the amino acids cystathionine, homocysteine, and cysteine by the action of at least two distinct enzymes: cystathionine-γ-lyase and cystathionine-β-synthase. In the past few years, H2S has emerged as a novel and increasingly important biological mediator. Imbalances in H2S have also been shown to be associated with various disease conditions. However, defining the precise pathophysiology of H2S is proving to be a complex challenge. Recent research in our laboratory has shown H2S as a novel mediator of inflammation and work in several groups worldwide is currently focused on determining the role of H2S in inflammation. H2S has been implicated in different inflammatory conditions, such as acute pancreatitis, sepsis, joint inflammation, and chronic obstructive pulmonary disease (COPD). Active research on the role of H2S in inflammation will unravel the pathophysiology of its actions in inflammatory conditions and may help develop novel therapeutic approaches for several, as yet incurable, disease conditions.Scientifica. 01/2012; 2012:159680.
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ABSTRACT: Abstract Aim: The present study was designed to explore the effects of hydrogen sulfide (H2S) on Ca(2+) homeostasis in rat pancreatic acini. Results: Sodium hydrosulfide (NaHS; an H2S donor) induced a biphasic increase in the intracellular Ca(2+) concentration ([Ca(2+)]i) in a dose-dependent manner. The NaHS-induced [Ca(2+)]i elevation persisted with an EC50 of 73.3 μM in the absence of extracellular Ca(2+) but was abolished by thapsigargin, indicating that both Ca(2+) entry and Ca(2+) release contributed to the increase. The [Ca(2+)]i increase was markedly inhibited in the presence of NG-monomethyl L-arginine or 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), and diaminofluorescein-2/diaminofluorescein-2 triazole (DAF-2/DAF-2T) fluorometry demonstrated that nitric oxide (NO) was also produced by H2S in a dose-dependent manner with an EC50 of 64.8 μM, indicating that NO was involved in the H2S effect. The H2S-induced [Ca(2+)]i increase was inhibited by pretreatment with U73122, xestospongin C, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, KT5823, and GP2A, indicating that phospholipase C (PLC), the inositol 1,4,5-trisphosphate (IP3) receptor, soluble guanylate cyclase (sGC), protein kinase G (PKG), and Gq-protein play roles as intermediate components in the H2S-triggered intracellular signaling. Innovation: To our knowledge, our study is the first one highlighting the effect of H2S on intracellular Ca(2+) dynamics in pancreatic acinar cells. Moreover, a novel cascade was presumed to function via the synergistic interaction between H2S and NO. Conclusion: We conclude that H2S affects [Ca(2+)]i homeostasis that is mediated by H2S-evoked NO production via an endothelial nitric oxide synthase (eNOS)-NO-sGC-cyclic guanosine monophosphate-PKG-Gq-protein-PLC-IP3 pathway to induce Ca(2+) release, and this pathway is identical to the one we recently proposed for a sole effect of NO and the two gaseous molecules synergistically function to regulate Ca(2+) homeostasis. Antioxid. Redox Signal. 00, 000-000.Antioxidants & Redox Signaling 10/2013; · 8.20 Impact Factor
- Shock 01/2009; 31 (Suppl 17). · 2.61 Impact Factor