TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2

Suvi-Katri Leivonen, Konstantinos Lazaridis, Julie Decock, Andrew Chantry, Dylan R. Edwards, Veli-Matti Kähäri

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58 Citations (Scopus)


Transforming growth factor-β (TGF-β) promotes extracellular matrix deposition by down-regulating the expression of matrix degrading proteinases and upregulating their inhibitors. Tissue inhibitor of metalloproteinases (TIMP)-3 is an ECM-associated specific inhibitor of matrix degrading metalloproteinases. Here, we have characterized the signaling pathways mediating TGF-β-induced expression of TIMP-3. Basal and TGF-β-induced TIMP-3 mRNA expression was abolished in Smad4-deficient mouse embryonic fibroblasts and restoring Smad4 expression rescued the response. Inhibition of Smad signaling by expression of Smad7 and dominant negative Smad3 completely abolished TGF-β-elicited expression of TIMP-3 in human fibroblasts, whereas overexpression of Smad3 enhanced it. Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation with PD98059 and p38 mitogen-activated protein kinase activity by SB203580 resulted in suppression of TGF-β-induced TIMP-3 expression, indicating that ERK1/2 and p38 MAPK mediate the effect of TGF-β on TIMP-3 expression. Specific activation of p38α and ERK1/2 by constitutively active mutants of MKK3b or MEK1, respectively, and simultaneous co-expression of Smad3 resulted in induction of TIMP-3 expression in the absence of TGF-β indicating that Smad3 co-operates with p38 and ERK1/2 in the induction of TIMP-3 expression. These results demonstrate the complex interplay between Smad3, p38α, and ERK1/2 signaling in the regulation of TIMP-3 gene expression in fibroblasts, which may play a role in inflammation, tissue repair, and fibrosis.
Original languageEnglish
Article numbere57474
JournalPLoS One
Issue number2
Publication statusPublished - 28 Feb 2013
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    Edwards, D., Andreasen (Aarhus), P., Baker (Glasgow), A., Bierau (Oncomethylome), K., Binder (Vienna), B., Bode (Max-Planck Institute), W., Brand (Humboldt), K., Brandstetter (Proteros), H., Caschetto (IFOM), C., Dano (Finsen Laboratory), K., Dive (CEA), V., Foidart (Liege), J., Gomis-Rüth (IBMB), F. X., Kahari (Turku), V., Kos (KRKA), J., Krüger (Munich), A., Lah Turnsek (NIB), T., Leonard (Uni of London), G., Levy (Genoptics), Y., Lopez-Otin (Oviedo), C., Mueller (DKFZ), M., Murphy (Cambridge), G., Paridaens (Leuven), R., Peters (Freiburg), C., Ragno (Unina), P., Rio (GIE), M., Sauter (Basel), G., Slegers (Gent), G., Stopelli (IIGB), M. P., Taraboletti (Mario Negri), G., Terenius (Stockholm), L., Tryggvason (Karolinska), K. & Yiotakis (Athens), A.

    CEC (Framework 6)


    Project: Research

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