Prostaglandin E2 modulates TNF-alpha-induced MCP-1 synthesis in pancreatic acinar cells in a PKA-dependent manner.
Cyclooxygenase (COX)-2 is increased in human chronic pancreatitis. We recently demonstrated in a model of chronic pancreatitis (WBN/Kob rat) that inhibition of COX-2 activity reduces and delays pancreatic inflammation and fibrosis. Monocyte chemoattractant protein (MCP)-1 mRNA and PGE(2) were significantly reduced, correlating with a decreased infiltration of macrophages. MCP-1 plays an important role in the recruitment of macrophages to the site of tissue injury. The aim of our study is to identify mechanisms by which macrophages and acinar cells maintain an inflammatory reaction. The expression profile of E prostanoid receptors EP(1-4) and MCP-1 was analyzed by RT-PCR from pancreatic specimens and AR42J cells. MCP-1 secretion was detected by ELISA from rat pancreatic lobuli. We determined EP(1-4) mRNA levels in WBN/Kob rats with chronic pancreatic inflammation. Individual isoforms were highly increased in rat pancreas, concurrent with MCP-1 mRNA expression. In supernatants of pancreatic lobuli and AR42J cells, MCP-1 was detectable by ELISA. In the presence of TNF-alpha, MCP-1 was upregulated. Coincubation with PGE(2) enhanced the TNF-alpha-induced MCP-1 synthesis significantly. Similarly, TNF-alpha mRNA was synergistically upregulated by TNF-alpha and PGE(2). Furthermore, the synergistic effect of TNF-alpha and PGE(2) was abolished by inhibition of PKA but not of PKC. We conclude that EP receptors are upregulated during chronic pancreatic inflammation. PGE(2) modulates the TNF-alpha-induced MCP-1 synthesis and secretion from acinar cells. This synergistic effect is controlled by PKA. This mechanism might explain the COX-2-dependent propagation of pancreatic inflammation.
Sun
Li-Kang
LK
Pancreatitis Research Laboratory, Lab D34, Swiss Hepato-Pancreato-Biliary Center, Dept. of Visceral and Transplantation Surgery, Univ. Hospital, Raemistrasse 100, 8091 Zurich, Switzerland.
Reding
Theresia
T
Bain
Martha
M
Heikenwalder
Mathias
M
Bimmler
Daniel
D
Graf
Rolf
R
D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone