Signal transduction of MCP-1 expression induced by pancreatitis-associated ascitic fluid in pancreatic acinar cells.
Pancreatitis-associated ascitic fluid (PAAF) is known to contribute to the progression of acute pancreatitis (AP). We have investigated the capability of PAAF to activate the expression of MCP-1 in pancreatic acinar cells and the involvement of MAPK, NF-kappaB and STAT3 as downstream signalling transduction pathways. The actions of dexamethasone (Dx) and N-acetylcysteine (NAC) on the PAAF's acinar effects have also been evaluated. Acinar cells were incubated for 1 hr with PAAF collected from rats with severe AP induced by sodium taurocholate in the absence or presence of Dx (10(-7) M) or NAC (30 mM). MCP-1 mRNA expression, phospho-p38-MAPK, IkappaB alpha, nuclear p65 levels and nuclear translocation of STAT3 were analysed. In response to PAAF, overexpression of MCP-1, phosphorylation of p38-MAPK, degradation of IkappaB alpha and increases in p65 nuclear levels and STAT3 activity were found in acinar cells. PAAF-mediated MCP-1 up-regulation was completely suppressed by Dx and NAC. MAPK activation was only inhibited by NAC, NF-kappaB activation was repressed by Dx and NAC, and STAT3 pathway was strongly blocked by Dx and significantly reduced by NAC. In conclusion, acinar cells were activated by PAAF to produce MCP-1, mainly via NF-kappaB and STAT3 pathways. Both downstream pathways were targeted by Dx and NAC to repress the PAAF-mediated acinar MCP-1 up-regulation.
Ramudo
Laura
L
Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.
Yubero
Sara
S
Manso
Manuel A
MA
Vicente
Secundino
S
De Dios
Isabel
I
D000818:Animals; D001202:Ascitic Fluid / Q000378:metabolism*; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D016328:NF-kappa B / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010195:Pancreatitis / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018932:Chemokine CCL2; D016328:NF-kappa B; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases