PT  - JOURNAL ARTICLE
AU  - Yung-Hua Koh
AU  - Ramasamy Tamizhselvi
AU  - Madhav Bhatia
TI  - Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH<sub>2</sub>-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells
AID  - 10.1124/jpet.109.160416
DP  - 2010 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 940--948
VI  - 332
IP  - 3
4099  - http://jpet.aspetjournals.org/content/332/3/940.short
4100  - http://jpet.aspetjournals.org/content/332/3/940.full
SO  - J Pharmacol Exp Ther2010 Mar 01; 332
AB  - The neuropeptide substance P (SP) has emerged to be an important proinflammatory mediator in acute pancreatitis (AP). The presence of substance P and its receptor, neurokinin-1 receptor (NK1R) has been shown in the pancreas and the pancreatic acinar cells. In this study, we investigated the unexplored mechanisms that mediate SP and NK1R expression using an in vitro AP model. Pancreatic acinar cells were obtained from pancreas of male Swiss mice. Isolated cells were treated with caerulein to mimic secretagogue pancreatitis. A concentration-dependent study that subjected the cells to 60 min of stimulation by caerulein showed that SP and the transcript from its gene preprotachykinin-A (PPT-A), and NK1R were up-regulated at a supraphysiological concentration of 10−7 M. A concentration-dependent study on intracellular kinases, extracellular signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK) and also transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) showed that they were activated when the caerulein concentration was 10−7 M. Inhibition of JNK reversed the up-regulation of PPT-A, SP, and NK1R. However, inhibition of ERK1/2 reversed the up-regulation of NK1R but not of PPT-A and SP. Furthermore, we found that specific ERK1/2 and JNK inhibitors reduce NF-κB and AP-1 activity. Taken together, our results suggest that supraphysiological concentrations of caerulein up-regulate the expression of SP and NK1R in pancreatic acinar cells, and the signaling molecules that are involved in this up-regulation include ERK1/2, JNK, NF-κB, and AP-1.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics