Preprotachykinin-A Gene Deletion Regulates Hydrogen Sulfide-Induced Toll-Like Receptor 4 Signaling Pathway in Cerulein-Treated Pancreatic Acinar Cells

Objective: This study aimed to determine the effect of hydrogen sulfide (H2S) on Toll-like receptor 4 (TLR4)-mediated innate immune signaling in acute pancreatitis (AP) via substance P. Methods: Male Swiss mice were treated with hourly intraperitoneal injections of cerulein (50 Kg/kg) for 10 hours. DL-propargylglycine ([PAG] 100 mg/kg, intraperitoneally), an inhibitor of H2S formation, was administered 1 hour after the induction of AP. Pancreatic acinar cells from male preprotachykinin-A gene-knockout mice (PPTA(-/-)) and their wild-type counterparts were incubated with or without cerulein (10(-7) M for 60 minutes). To better understand the effect of H2S in inflammation, acinar cells were stimulated with cerulein after addition of H2S donor, sodium hydrosulfide. In addition, cerulein-treated pancreatic acinar cells were pretreated with PAG (30 KM) for 1 hour. Results: The H2S inhibitor PAG eliminated TLR4, interleukin 1 receptor-associated kinase 4, tumor necrosis factor receptor-associated factor 6, and nuclear factor-kappa B (NF-kappa B) levels in in vitro and in vivo models of cerulein-induced AP. PPTA gene deletion reduced TLR4, myeloid differentiation factor 88, interleukin 1 receptor-associated kinase 4, tumor necrosis factor receptor-associated factor 6, and NF-kappa B in cerulein-treated pancreatic acinar cells, whereas administration of sodium hydrosulfide resulted in a further rise in TLR4 and NF-kappa B levels in cerulein-treated pancreatic acinar cells. Conclusion: The present findings show for the first time that in AP, H2S may up-regulate the TLR4 pathway and NF-kappa B via substance P.