Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts

Abstract

Background & aims: We have previously isolated and characterized human pancreatic periacinar myofibroblasts. In this study, to define the role of these cells in the pathogenesis of acute pancreatitis, we investigated chemokine expression in them.

Methods: Secretion of chemokines (interleukin [IL]-8, monocyte chemoattractant protein [MCP]-1, RANTES, and MIP [macrophage inflammatory protein]-1alpha) was evaluated by ELISA, Northern blotting, and nuclear run-on assays. The activation of NF-kappaB and NF-IL6 was assessed by an electrophoretic gel mobility shift assay.

Results: IL-8 and MCP-1 secretion was rapidly induced by both IL-1beta and tumor necrosis factor (TNF)-alpha. RANTES secretion was induced more slowly and was induced mainly by TNF-alpha. However, MIP-1alpha secretion was not induced by any stimuli. These responses were also observed at the messenger RNA level, and they were accompanied by an increase in transcriptional rate. The increase in transcriptional activation of chemokine genes correlated with the NF-kappaB and NF-IL6 activation. Furthermore, a blockade of NF-kappaB activation by PDTC and TPCK markedly reduced the IL-1beta- or TNF-alpha-induced chemokine gene expression.

Conclusions: Chemokine secretion is differentially regulated in pancreatic periacinar myofibroblasts, suggesting a role for these cells in mediating the infiltration and accumulation of inflammatory cells in the pancreas.