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Prostaglandin E₂ modulates TNF--induced MCP-1 synthesis in pancreatic acinar cells in a PKA-dependent manner

¹Pancreatitis Research Laboratory, Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, and ²Department Pathology, University Hospital, Zurich, Switzerland

Submitted 20 July 2007 ; accepted in final form 4 October 2007

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 PGE₂ 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-, MCP-1 was upregulated. Coincubation with PGE₂ enhanced the TNF--induced MCP-1 synthesis significantly. Similarly, TNF- mRNA was synergistically upregulated by TNF- and PGE₂. Furthermore, the synergistic effect of TNF- and PGE₂ was abolished by inhibition of PKA but not of PKC. We conclude that EP receptors are upregulated during chronic pancreatic inflammation. PGE₂ modulates the TNF--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.

chronic pancreatitis; monocyte chemotactic protein-1; tumor necrosis factor-; E prostanoid receptors 1-4

This article has been cited by other articles:

				T. Reding, U. Wagner, A. B. Silva, L-K. Sun, M. Bain, S.-Y. Kim, D. Bimmler, and R. Graf Inflammation-dependent expression of SPARC during development of chronic pancreatitis in WBN/Kob rats and a microarray gene expression analysis Physiol Genomics, July 9, 2009; 38(2): 196 - 204. [Abstract] [Full Text] [PDF]