Matrix metalloproteinase-3 secretion from human pancreatic periacinar myofibroblasts in response to inflammatory mediators

OBJECTIVES: Matrix metalloproteinases (MMPs) play roles in the pathophysiology of pancreatic disorders. However, the regulation of MMP-3 secretion in the pancreas remains unclear. In this study, we assessed the expression of MMP-3 in human pancreatic periacinar myofibroblasts. METHODS: MMP-3 secretion and MMP-3 mRNA expression were determined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. RESULTS: In human pancreatic myofibroblasts, MMP-3 secretion and mRNA expression were induced by interleukin (IL)-17, IL-1β, and tumor necrosis factor (TNF) -α, respectively. The effects of IL-17 were detected as similar in extent to those induced by IL-1β or TNF-α. Costimulation by IL-17 plus IL-1β and/or IL-17 plus TNF-α induced a synergistic increase in MMP-3 secretion, although the costimulatory effects of these combinations were not detected in tissue inhibitor of matrix metalloproteinase-1 secretion. Adenovirus-mediated transfer of a stable form of IκBα markedly inhibited the effects of IL-17, IL-1β, and TNF-α. Mitogen-activated protein kinase inhibitors (U0126, PD098059, and SB203580) also blocked MMP-3 secretion. These findings indicate a role for nuclear factor-κB and mitogen-activated protein kinases in cytokine-induced MMP-3 secretion. CONCLUSIONS: Pancreatic periacinar myofibroblasts actively secrete MMP-3 in response to IL-17, IL-1β, and TNF-α. Pancreatic myofibroblasts may play an important role in extracellular matrix turnover via MMP-3 secretion in the pancreas.