Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen.
Located within the perisinusoidal space and surrounded by extracellular matrix, hepatic stellate cells (HSC) undergo phenotypic trans-differentiation called "myofibroblastic activation" in liver fibrogenesis. This study investigated the regulation of interleukin-1 (IL-1alpha) on expression of matrix metalloproteinases (MMPs) by HSC grown in three-dimensional extracellular matrix and the role of MMPs in HSC activation. To recapitulate the in vivo "quiescent" state of HSC, the isolated rat HSC were grown in three-dimensional Matrigel or type I collagen. Stimulation with IL-1alpha caused robust induction of pro-MMP-9 (the precursor of matrix metalloproteinase-9) when HSC were cultured in these matrices. IL-1alpha induced a conversion of the pro-MMP-9 to the active form only when the cells were in type I collagen. In collagen lattices, IL-1alpha provoked activation of HSC with induction of MMP-13, MMP-3, and breakdown of the matrix. The HSC activation was completely prevented by a treatment of the cells with tissue inhibitor of metalloproteinase-1 or deprivation of MMP-9. Once fully activated, HSC failed to express MMP-9 and showed attenuated induction of MMP-13 and MMP-3. Further, we demonstrated colocalization of alpha-smooth muscle actin and MMP-9 in a subpopulation of HSC in human fibrotic liver tissues. Thus, this study provides a novel model to enlighten the role of MMPs, particularly that of MMP-9, in HSC activation regulated by a specific cytokine in liver fibrogenesis.
Han
Yuan-Ping
YP
Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of Medicine of University of Southern California, Los Angeles, California 90033, USA. yhan@surgery.usc.edu
Zhou
Ling
L
Wang
Jiaohong
J
Xiong
Shigang
S
Garner
Warren L
WL
French
Samuel W
SW
Tsukamoto
Hidekazu
H
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D007375:Interleukin-1; D003094:Collagen; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9