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Inhibition of Connective Tissue Growth Factor/CCN2 Expression in Human Dermal Fibroblasts by Interleukin-1 alpha and beta
Dept Surg Sci, Plast Surg Unit, Uppsala Univ, Uppsala, Sweden.
Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden. (Örebro Life Sci Ctr, Örebro, Sweden)ORCID iD: 0000-0001-8304-2772
Dept Surg Sci, Plast Surg Unit, Uppsala Univ, Uppsala, Sweden.
Dept Surg Sci, Plast Surg Unit, Uppsala Univ, Uppsala, Sweden.
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2010 (English)In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 110, no 5, p. 1226-1233Article in journal (Refereed) Published
Abstract [en]

Connective tissue growth factor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor (TGF)-beta and intimately involved with tissue repair and overexpressed in various fibrotic conditions We previously showed that keratmocytes in vitro downregulate TGF-beta-induced expression of CTGF in fibroblasts by an interleukin (IL)-1 alpha-dependent mechanism. Here, we investigated further the mechanisms of this downregulation by both IL-1 alpha and beta Human dermal fibroblasts and NIH 3T3 cells were treated with IL-1 alpha or beta in presence or absence of TGF-beta 1. IL-1 suppressed basal and TGF-beta-induced CTGF mRNA and protein expression. IL-1 alpha and beta inhibited TGF-beta-stimulated CTGF promoter activity, and the activity of a synthetic minimal promoter containing Smad 3-binding CAGA elements Furthermore. IL-1 alpha and beta inhibited TGF-beta-stimulated Smad 3 phosphorylation, possibly linked to an observed increase in Smad 7 mRNA expression. In addition. RNA interference suggested that TGF-beta activated kinase1 (TAK1) is necessary for IL-1 inhibition of TGF-beta-stimulated CTGF expression. These results add to the understanding of how the expression of CTGF in human dermal fibroblasts is regulated, which in turn may have implications for the pathogenesis of fibrotic conditions involving the skin. J. Cell Biochem. 110: 1226-1233, 2010. (C) 2010 Wiley-Liss. Inc

Place, publisher, year, edition, pages
2010. Vol. 110, no 5, p. 1226-1233
Keywords [en]
interleukin-1, connective tissue growth factor, transforming growth factor-beta, smad 3, tak1
National Category
Cell Biology Biochemistry and Molecular Biology
Research subject
Cell Research
Identifiers
URN: urn:nbn:se:oru:diva-28379DOI: 10.1002/jcb.22637ISI: 000280435900021PubMedID: 20544797Scopus ID: 2-s2.0-77954894569OAI: oai:DiVA.org:oru-28379DiVA, id: diva2:613115
Available from: 2013-03-26 Created: 2013-03-14 Last updated: 2018-04-24Bibliographically approved
In thesis
1. Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α: studies in two- and three dimensional in vitro models
Open this publication in new window or tab >>Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α: studies in two- and three dimensional in vitro models
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dysregulated wound healing is commonly associated with excessive fibrosis. Connective tissue growth factor (CTGF/CCN2) is characteristically overexpressed in fibrotic diseases and stimulated by transforming growth factor-β (TGF-β) in dermal fibroblasts. Reepithelialisation and epidermal wound coverage counteract excessive scar formation. We have previously shown that interleukin-1α (IL-1α) derived from keratinocytes conteracts TGF-β-stimulated CTGF-expression. The aim of this thesis was to further explore the effects of keratinocytes and IL-1α on gene and protein expression, as well as pathways, in TGF-β stimulated fibroblasts. Fibroblasts were studied in vitro by conventional two dimensional cell culture models and in a three dimensional keratinocyte-fibroblast organotypic skin culture model.

The results showed that IL-1 suppresses basal and TGF-β-induced CTGF mRNA and protein, involving a possible TAK1 mechanism. Keratinocytes regulate the expression of fibroblast genes important for the turnover of the extracellular matrix. Most of the genes analysed (11/13) were regulated by TGF-β and counter regulated by keratinocytes. The overall results support a view that keratinocytes regulate fibroblasts to act catabolically (anti-fibrotic) on the extracellular matrix.

Transcriptional microarray and gene set enrichment analysis showed that antagonizing effects of IL-1α on TGF-β were much more prominent than the synergistic effects. The most confident of these pathways was the interferon signaling, which were inhibited by TGF-β and activated by IL-1α. A proteomics study confirmed that IL-1α preferentially conteracts TGF-β effects. Six new fibroblast proteins involved in synthesis/ regulation were identified, being regulated by TGF-β and antagonized by IL-1α. Pathway analysis confirmed counter-regulation of interferon signaling by the two cytokines. These findings have implications for understanding the role of fibroblasts for inflammatory responses and development of fibrosis in the skin.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2016. p. 83
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 133
Keywords
Fibroblast, Keratinocyte, TGF-β, IL-1α, coculture, fibrosis CTGF/CNN 2, dermal, organotypic culture
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:oru:diva-48225 (URN)978-91-7529-120-8 (ISBN)
Public defence
2016-03-18, Universitetssjukhuset, Wilandersalen, Södra Grev Rosengatan, Örebro, 09:00 (English)
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Available from: 2016-02-12 Created: 2016-02-12 Last updated: 2018-01-10Bibliographically approved

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Koskela, AnitaIvarsson, Mikael

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