Proteasome blockade exerts an antifibrotic activity by coordinately down-regulating type I collagen and tissue inhibitor of metalloproteinase-1 and up-regulating metalloproteinase-1 production in human dermal fibroblasts.
Tissue fibrosis results when dysregulation of extracellular matrix (ECM) turnover favors deposition of collagen and other ECM proteins over degradation. Fibrosis may then lead to organ dysfunction and pathology as observed in systemic sclerosis (SSc). In the present study, we investigated the antifibrotic properties of proteasome blockade. A dose- and time-dependent reduction in type-I collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) production was observed in normal fibroblasts exposed to proteasome inhibitors (PI). In the same culture conditions, metalloproteinase-1 (MMP-1) protein and the collagenolytic activity on type I collagen was increased. The steady-state mRNA levels of COL1A1, TIMP-1, and MMP-1 paralleled protein levels. These effects were dominant over the profibrotic properties of TGF-beta and were observed with fibroblasts generated from normal and SSc skin. PI decreased type I collagen mRNA levels with kinetics similar to those observed with DRB, a specific RNA polymerase II inhibitor, thus indicating transcriptional inhibition. Of interest, PI induced c-Jun phosphorylation and c-Jun nuclear accumulation. The specific N-terminal Jun-kinase inhibitor SP-600125 selectively abrogated c-Jun phosphorylation and, in a dose-dependent fashion, the up-regulated synthesis of MMP-1 induced by PI. Finally, PI did not affect fibroblast viability. Thus, the coordinated down-regulation of collagen and TIMP-1 and up-regulation of MMP-1 renders proteasome blockade an attractive strategy for treating conditions as SSc, characterized by excessive fibrosis.
Fineschi
Serena
S
Immunology and Allergy, Department of Internal Medicine, Geneva University Hospital, Geneva School of Medicine, Geneva, Switzerland.
Reith
Walter
W
Guerne
Pierre André
PA
Dayer
Jean-Michel
JM
Chizzolini
Carlo
C
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis; D016758:Genes, jun; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012595:Scleroderma, Systemic / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000873:Anthracenes; D001897:Boronic Acids; D024042:Collagen Type I; D007976:Leupeptins; D061988:Proteasome Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D011719:Pyrazines; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; C067713:lactacystin; C432165:pyrazolanthrone; D000069286:Bortezomib; D048031:JNK Mitogen-Activated Protein Kinases; D012319:RNA Polymerase II; D020781:Matrix Metalloproteinase 1; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine