Pro-inflammatory cytokine-induced matrix metalloproteinase-1 (MMP-1) secretion in human pancreatic periacinar myofibroblasts.
Matrix metalloproteinases (MMPs) are the proteases involved in the degradation of the extracellular matrix. MMP-1 is thought to be one of the key enzymes in fibrolysis, a process closely related to tissue remodeling. In the present study, we investigated MMP-1 secretion from human pancreatic periacinar myofibroblasts in response to pro-inflammatory cytokines IL-1beta and TNF-alpha. We also attempted to clarify the intracellular signaling pathways mediating the cytokine-induced MMP-1 secretion. MMP-1 secretion was measured by an enzyme-linked immunosorbent assay. MMP-1 molecules were analyzed by Western blotting. MMP-1 mRNA expression was evaluated by Northern blotting. IL-1l and TNF-alpha stimulated the MMP-1 secretion in a dose- and time-dependent manner. Ninety percent of MMP-1 was secreted as inactive form (pro-MMP-1). The effects of IL-1beta and TNF-alpha were significantly inhibited by PD98059 MEK/ERK inhibitor). In contrast, SB203580 (p38 MAPK inhibitor), GF109203X (PKC inhibitor), and PDTC (NF-kappaB inhibitor) did not alter the MMP-1 secretion induced by IL-1beta and TNF-alpha. These effects were also observed at them RNA level. In conclusion, in human pancreatic periacinar myofibroblasts, MMP-1 secretion was regulated by the pro-inflammatory cytokines via the MEK/ERK cascade. Thus, human pancreatic periacinar myofibroblasts may play an important role in the remodeling of damaged pancreatic tissue in chronic pancreatitis via MMP-1 secretion.
Tasaki
Kazuhito
K
Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan. kazut@belle.shiga-med.ac.jp
Shintani
Yutaka
Y
Saotome
Takao
T
Andoh
Akira
A
Fujiyama
Yoshihide
Y
Hozawa
Shigenari
S
Bamba
Tadao
T
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008301:Maleimides / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010179:Pancreas / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D007375:Interleukin-1; D008301:Maleimides; D016328:NF-kappa B; D011725:Pyridines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D011392:Proline; D020928:Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; C070515:bisindolylmaleimide I; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one