title: Preprotachykinin-A gene deletion regulates hydrogen sulfide-induced toll-like receptor 4 signaling pathway in cerulein-treated pancreatic acinar cells.
abstract: 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 μg/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 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 μM) 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-κB (NF-κB) 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-κB in cerulein-treated pancreatic acinar cells, whereas administration of sodium hydrosulfide resulted in a further rise in TLR4 and NF-κB levels in cerulein-treated pancreatic acinar cells.
  
  
  CONCLUSIONS
  The present findings show for the first time that in AP, H2S may up-regulate the TLR4 pathway and NF-κB via substance P.
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Tamizhselvi
authors.forename: Pratima
authors.initials: P
authors.lastname: Shrivastava
authors.forename: Yung-Hua
authors.initials: YH
authors.lastname: Koh
authors.forename: Huili
authors.initials: H
authors.lastname: Zhang
authors.forename: Madhav
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000208:Acute Disease; D000818:Animals; D001483:Base Sequence; D002108:Ceruletide / Q000633:toxicity; D017931:DNA Primers / Q000235:genetics; D017353:Gene Deletion; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011498:Protein Precursors / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013373:Substance P / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D015320:Tachykinins / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017931:DNA Primers; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011498:Protein Precursors; D048029:TNF Receptor-Associated Factor 6; D015320:Tachykinins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C044206:preprotachykinin; D013373:Substance P; D002108:Ceruletide; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D006862:Hydrogen Sulfide