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Effect of mitogen-activated protein kinases on chemokine synthesis induced by substance P in mouse pancreatic acinar cells.

Ramnath RD, Sun J, Adhikari S, Bhatia M - J. Cell. Mol. Med. (2007 Nov-Dec)

Bottom Line: Moreover, substance P-induced ERK 1/2, JNK, NFkappaB and AP-1 activation as well as chemokine synthesis were blocked by pre-treatment with either extracellular signal-regulated protein kinase kinase 1 (MEK1) inhibitor or JNK inhibitor.In addition, substance P-induced activation of ERK 112, JNK, NFkappaB and AP-1-driven chemokine production were attenuated by CP96345, a selective NK1 R antagonist, in pancreatic acinar cells.Taken together, these results suggest that substance P-NK1 R induced chemokine production depends on the activation of MAPKs-mediated NFkappaB and AP-1 signalling pathways in mouse pancreatic acini.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, National University of Singapore, Singapore.

ABSTRACT
Substance P, acting via its neurokinin 1 receptor (NK1 R), plays an important role in mediating a variety of inflammatory processes. Its interaction with chemokines is known to play a crucial role in the pathogenesis of acute pancreatitis. In pancreatic acinar cells, substance P stimulates the release of NFkappaB-driven chemokines. However, the signal transduction pathways by which substance P-NK1 R interaction induces chemokine production are still unclear. To that end, we went on to examine the participation of mitogen-activated protein kinases (MAPKs) in substance P-induced synthesis of pro-inflammatory chemokines, monocyte chemoanractant protein-1 (MCP-I), macrophage inflammatory protein-lalpha (MIP-lalpha) and macrophage inflammatory protein-2 (MIP-2), in pancreatic acini. In this study, we observed a time-dependent activation of ERK1/2, c-Jun N-terminal kinase (JNK), NFkappaB and activator protein-1 (AP-1) when pancreatic acini were stimulated with substance P. Moreover, substance P-induced ERK 1/2, JNK, NFkappaB and AP-1 activation as well as chemokine synthesis were blocked by pre-treatment with either extracellular signal-regulated protein kinase kinase 1 (MEK1) inhibitor or JNK inhibitor. In addition, substance P-induced activation of ERK 112, JNK, NFkappaB and AP-1-driven chemokine production were attenuated by CP96345, a selective NK1 R antagonist, in pancreatic acinar cells. Taken together, these results suggest that substance P-NK1 R induced chemokine production depends on the activation of MAPKs-mediated NFkappaB and AP-1 signalling pathways in mouse pancreatic acini.

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A schematic representation of the signalling cascade that mediates substance P-NK1-R induced chemokine production in pancreatic acinar cells. Substance P (SP) induces activation of MAP kinases ERK and JNK in pancreatic acinar cells. Moreover, substance P-induced phosphorylation of ERK and JNK mediates the activation of transcription factors NFκB and AP-1, thus resulting in increased secretion of pro-inflammatory mediators MCP- 1, MIP-1α and MIP-2 in acinar cells. Substance P-induced ERK1/2, JNK, NFκB, AP-1 activation and chemokine synthesis are depended on NK1R.
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fig10: A schematic representation of the signalling cascade that mediates substance P-NK1-R induced chemokine production in pancreatic acinar cells. Substance P (SP) induces activation of MAP kinases ERK and JNK in pancreatic acinar cells. Moreover, substance P-induced phosphorylation of ERK and JNK mediates the activation of transcription factors NFκB and AP-1, thus resulting in increased secretion of pro-inflammatory mediators MCP- 1, MIP-1α and MIP-2 in acinar cells. Substance P-induced ERK1/2, JNK, NFκB, AP-1 activation and chemokine synthesis are depended on NK1R.

Mentions: To further understand the molecular mechanism and to show that substance P-induced chemokine production was indeed mediated by substance P, and not by some non-specific effects upon acinar cells isolation, we pre-treated the cells with the selective NK1R antagonist, CP96345. In the present study, CP96345 decreased the activation of ERK1/2, JNK, NFκB and AP-1 mediated chemokine production, hence showing that substance P-induced chemokine production is dependent on NK1R in pancreatic aci-nar cells. Based on our results, we proposed the mechanism by which substance P induces chemokine production in mouse pancreatic acinar cells (Fig. 10).


Effect of mitogen-activated protein kinases on chemokine synthesis induced by substance P in mouse pancreatic acinar cells.

Ramnath RD, Sun J, Adhikari S, Bhatia M - J. Cell. Mol. Med. (2007 Nov-Dec)

A schematic representation of the signalling cascade that mediates substance P-NK1-R induced chemokine production in pancreatic acinar cells. Substance P (SP) induces activation of MAP kinases ERK and JNK in pancreatic acinar cells. Moreover, substance P-induced phosphorylation of ERK and JNK mediates the activation of transcription factors NFκB and AP-1, thus resulting in increased secretion of pro-inflammatory mediators MCP- 1, MIP-1α and MIP-2 in acinar cells. Substance P-induced ERK1/2, JNK, NFκB, AP-1 activation and chemokine synthesis are depended on NK1R.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401295&req=5

fig10: A schematic representation of the signalling cascade that mediates substance P-NK1-R induced chemokine production in pancreatic acinar cells. Substance P (SP) induces activation of MAP kinases ERK and JNK in pancreatic acinar cells. Moreover, substance P-induced phosphorylation of ERK and JNK mediates the activation of transcription factors NFκB and AP-1, thus resulting in increased secretion of pro-inflammatory mediators MCP- 1, MIP-1α and MIP-2 in acinar cells. Substance P-induced ERK1/2, JNK, NFκB, AP-1 activation and chemokine synthesis are depended on NK1R.
Mentions: To further understand the molecular mechanism and to show that substance P-induced chemokine production was indeed mediated by substance P, and not by some non-specific effects upon acinar cells isolation, we pre-treated the cells with the selective NK1R antagonist, CP96345. In the present study, CP96345 decreased the activation of ERK1/2, JNK, NFκB and AP-1 mediated chemokine production, hence showing that substance P-induced chemokine production is dependent on NK1R in pancreatic aci-nar cells. Based on our results, we proposed the mechanism by which substance P induces chemokine production in mouse pancreatic acinar cells (Fig. 10).

Bottom Line: Moreover, substance P-induced ERK 1/2, JNK, NFkappaB and AP-1 activation as well as chemokine synthesis were blocked by pre-treatment with either extracellular signal-regulated protein kinase kinase 1 (MEK1) inhibitor or JNK inhibitor.In addition, substance P-induced activation of ERK 112, JNK, NFkappaB and AP-1-driven chemokine production were attenuated by CP96345, a selective NK1 R antagonist, in pancreatic acinar cells.Taken together, these results suggest that substance P-NK1 R induced chemokine production depends on the activation of MAPKs-mediated NFkappaB and AP-1 signalling pathways in mouse pancreatic acini.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, National University of Singapore, Singapore.

ABSTRACT
Substance P, acting via its neurokinin 1 receptor (NK1 R), plays an important role in mediating a variety of inflammatory processes. Its interaction with chemokines is known to play a crucial role in the pathogenesis of acute pancreatitis. In pancreatic acinar cells, substance P stimulates the release of NFkappaB-driven chemokines. However, the signal transduction pathways by which substance P-NK1 R interaction induces chemokine production are still unclear. To that end, we went on to examine the participation of mitogen-activated protein kinases (MAPKs) in substance P-induced synthesis of pro-inflammatory chemokines, monocyte chemoanractant protein-1 (MCP-I), macrophage inflammatory protein-lalpha (MIP-lalpha) and macrophage inflammatory protein-2 (MIP-2), in pancreatic acini. In this study, we observed a time-dependent activation of ERK1/2, c-Jun N-terminal kinase (JNK), NFkappaB and activator protein-1 (AP-1) when pancreatic acini were stimulated with substance P. Moreover, substance P-induced ERK 1/2, JNK, NFkappaB and AP-1 activation as well as chemokine synthesis were blocked by pre-treatment with either extracellular signal-regulated protein kinase kinase 1 (MEK1) inhibitor or JNK inhibitor. In addition, substance P-induced activation of ERK 112, JNK, NFkappaB and AP-1-driven chemokine production were attenuated by CP96345, a selective NK1 R antagonist, in pancreatic acinar cells. Taken together, these results suggest that substance P-NK1 R induced chemokine production depends on the activation of MAPKs-mediated NFkappaB and AP-1 signalling pathways in mouse pancreatic acini.

Show MeSH
Related in: MedlinePlus