1. Essential Role of Matrix Metalloproteinases in Interleukin-1-induced Myofibroblastic Activation of Hepatic Stellate Cell in Collagen
- Author
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Hidekazu Tsukamoto, Samuel W. French, Warren L. Garner, Ling Zhou, Jiaohong Wang, Yuan-Ping Han, and Shigang Xiong
- Subjects
Liver Cirrhosis ,Male ,Cellular differentiation ,medicine.medical_treatment ,In Vitro Techniques ,Matrix metalloproteinase ,Biochemistry ,Article ,Extracellular matrix ,medicine ,Animals ,Humans ,Rats, Wistar ,Molecular Biology ,Matrigel ,Chemistry ,Cell Differentiation ,hemic and immune systems ,Cell Biology ,Matrix Metalloproteinases ,Rats ,Cell biology ,Perisinusoidal space ,Cytokine ,Matrix Metalloproteinase 9 ,Immunology ,Hepatocytes ,Hepatic stellate cell ,Collagen ,Type I collagen ,Interleukin-1 - Abstract
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.
- Published
- 2004