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Induction of myofibroblast MMP-9 transcription in three-dimensional collagen I gel cultures: regulation by NF-kappaB, AP-1 and Sp1

Lookup NU author(s): Professor Fiona Oakley, Professor Derek Mann

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Abstract

Chronic liver injury leads to a progressive wound healing response that eventually results in hepatic fibrosis characterised by net deposition of fibrillar extracellular matrix (ECM) and a qualitative shift from type IV to type I/III collagen. The pivotal cellular event underlying this response is hepatic stellate cell (HSC) activation towards a myofibroblast-like phenotype. Activated HSC contribute to ECM remodelling via secretion of type I/III collagens and matrix metalloproteinases (MMPs). Previous studies showed that three-dimensional (3D) contact of activated HSC with type I collagen further stimulates the ECM remodelling properties of HSC by inducing the type IV gelatinase, MMP-9. The aim of the current study was to confirm transcriptional activation of the MMP-9 gene and identify transcription factors regulating this response. Gelatin zymography and Northern blotting were used to confirm induction of MMP-9 protein and mRNA expression in primary rat HSC cultured in a three-dimensional collagen I gel lattice. MMP-9 promoter studies in transfected HSC and electrophoretic mobility shift assay (EMSA) were employed to study transcriptional events. Both NF-kappaB and AP-1 DNA were induced in HSC cultured in 3D collagen I gels and binding sites for these factors in the MMP-9 promoter were crucial for induction of transcription. By contrast removal of an Sp1 site in the promoter enhanced transcription, while over-expression of either Sp1 or Sp3 repressed transcription. It is concluded that 3D contact of activated HSC with collagen I stimulates MMP-9 expression by elevating NF-kappaB and AP-1 activities which are able to overcome the repressive influence of Sp1/Sp3 on MMP-9 gene transcription.


Publication metadata

Author(s): Takahra T, Smart DE, Oakley F, Mann DA

Publication type: Article

Publication status: Published

Journal: International Journal of Biochemistry & Cell Biology

Year: 2004

Volume: 36

Issue: 2

Pages: 353-363

ISSN (print): 1357-2725

ISSN (electronic): 1878-5875

Publisher: Pergamon

URL: http://dx.doi.org/10.1016/S1357-2725(03)00260-7

DOI: 10.1016/S1357-2725(03)00260-7


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