title: Activation of neurokinin-1 receptors up-regulates substance P and neurokinin-1 receptor expression in murine pancreatic acinar cells.
abstract: Acute pancreatitis (AP) has been associated with an up-regulation of substance P (SP) and neurokinin-1 receptor (NK1R) in the pancreas. Increased SP-NK1R interaction was suggested to be pro-inflammatory during AP. Previously, we showed that caerulein treatment increased SP/NK1R expression in mouse pancreatic acinar cells, but the effect of SP treatment was not evaluated. Pancreatic acinar cells were obtained from pancreas of male swiss mice (25-30 g). We measured mRNA expression of preprotachykinin-A (PPTA) and NK1R following treatment of SP (10(-6) M). SP treatment increased PPTA and NK1R expression in isolated pancreatic acinar cells, which was abolished by pretreatment of a selective NK1R antagonist, CP96,345. SP also time dependently increased protein expression of NK1R. Treatment of cells with a specific NK1R agonist, GR73,632, up-regulated SP protein levels in the cells. Using previously established concentrations, pre-treatment of pancreatic acinar cells with Gö6976 (10 nM), rottlerin (5 μM), PD98059 (30 μM), SP600125 (30 μM) or Bay11-7082 (30 μM) significantly inhibited up-regulation of SP and NK1R. These observations suggested that the PKC-ERK/JNK-NF-κB pathway is necessary for the modulation of expression levels. In comparison, pre-treatment of CP96,345 reversed gene expression in SP-induced cells, but not in caerulein-treated cells. Overall, the findings in this study suggested a possible auto-regulatory mechanism of SP/NK1R expression in mouse pancreatic acinar cells, via activation of NK1R. Elevated SP levels during AP might increase the occurrence of a positive feedback loop that contributes to abnormally high expression of SP and NK1R.
authors: Department of Pharmacology, National University of Singapore, Singapore.
authors: Yung-Hua
authors: YH
authors: Koh
authors: Shabbir
authors: S
authors: Moochhala
authors: Madhav
authors: M
authors: Bhatia
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D061354:Acinar Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002478:Cells, Cultured; D002108:Ceruletide / Q000494:pharmacology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P / Q000235:genetics* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000098:Acetophenones; D001578:Benzopyrans; D016328:NF-kappa B; D009570:Nitriles; D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; D013450:Sulfones; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; D002108:Ceruletide; C085746:rottlerin