Matrix metalloproteinase-3 secretion from human pancreatic periacinar myofibroblasts in response to inflammatory mediators.
OBJECTIVE
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-1beta, and tumor necrosis factor (TNF) -alpha, respectively. The effects of IL-17 were detected as similar in extent to those induced by IL-1beta or TNF-alpha. Costimulation by IL-17 plus IL-1beta and/or IL-17 plus TNF-alpha 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 IkappaBalpha markedly inhibited the effects of IL-17, IL-1beta, and TNF-alpha. Mitogen-activated protein kinase inhibitors (U0126, PD098059, and SB203580) also blocked MMP-3 secretion. These findings indicate a role for nuclear factor-kappaB 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-1beta, and TNF-alpha. Pancreatic myofibroblasts may play an important role in extracellular matrix turnover via MMP-3 secretion in the pancreas.
Inatomi
Osamu
O
Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan.
Andoh
Akira
A
Yagi
Yuhki
Y
Ogawa
Atsuhiro
A
Hata
Kazunori
K
Shiomi
Hisanori
H
Tani
Tohru
T
Takayanagi
Atsushi
A
Shimizu
Nobuyoshi
N
Fujiyama
Yoshihide
Y
D000256:Adenoviridae / Q000235:genetics; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D018014:Gene Transfer Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D020381:Interleukin-17 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D010179:Pancreas / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018836:Inflammation Mediators; D020381:Interleukin-17; D053583:Interleukin-1beta; D016328:NF-kappa B; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D020929:Mitogen-Activated Protein Kinase Kinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one