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

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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
Volume8
Issue number2
DOIs
Publication statusPublished - 28 Feb 2013
Externally publishedYes

Fingerprint

Tissue Inhibitor of Metalloproteinase-3
transforming growth factors
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Transforming Growth Factors
metalloproteinases
Fibroblasts
mitogen-activated protein kinase
fibroblasts
p38 Mitogen-Activated Protein Kinases
Chemical activation
Matrix Metalloproteinase Inhibitors
Military electronic countermeasures
tissues
Metalloproteases
Extracellular Matrix
Gene expression
tissue repair
fibrosis
Fibrosis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

TGF-β-Elicited Induction of Tissue Inhibitor of Metalloproteinases (TIMP)-3 Expression in Fibroblasts Involves Complex Interplay between Smad3, p38α, and ERK1/2. / Leivonen, Suvi Katri; Lazaridis, Konstantinos; Decock, Julie; Chantry, Andrew; Edwards, Dylan R.; Kähäri, Veli Matti.

In: PLoS One, Vol. 8, No. 2, e57474, 28.02.2013.

Research output: Contribution to journalArticle

Leivonen, Suvi Katri ; Lazaridis, Konstantinos ; Decock, Julie ; Chantry, Andrew ; Edwards, Dylan R. ; Kähäri, Veli Matti. / TGF-β-Elicited Induction of Tissue Inhibitor of Metalloproteinases (TIMP)-3 Expression in Fibroblasts Involves Complex Interplay between Smad3, p38α, and ERK1/2. In: PLoS One. 2013 ; Vol. 8, No. 2.
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