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Keratinocytes inhibit expression of connective tissue growth factor in vitro by an interleukin-1α-dependent mechanism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
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2002 In: Journal of Investigative Dermatology, ISSN 1523-1747, Vol. 119, no Aug 2, 449-55 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 119, no Aug 2, 449-55 p.
Identifiers
URN: urn:nbn:se:uu:diva-93188OAI: oai:DiVA.org:uu-93188DiVA: diva2:166590
Available from: 2005-05-13 Created: 2005-05-13 Last updated: 2015-03-17Bibliographically approved
In thesis
1. Regulation of Fibroblast Activity by Keratinocytes
Open this publication in new window or tab >>Regulation of Fibroblast Activity by Keratinocytes
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Keratinocyters påverkan på fibroblasters aktivitet
Abstract [en]

In the healing of cutaneous wounds, paracrine communication between keratinocytes and fibroblasts regulates cell differentiation, proliferation and synthesis of extracellular matrix. Deficient epidermal coverage, as seen in burn-wounds, frequently results in hypertrophic scars. Previous studies suggest that keratinocytes downregulate the production of collagen and profibrotic factors in fibroblasts. We hypothesized that keratinocytes downregulate the expression of the profibrotic factor connective tissue growth factor (CTGF) in fibroblasts, and regulate fibroblast expression of genes important to wound healing. In keratinocyte-fibroblast cocultures, keratinocytes downregulated CTGF mRNA and protein in fibroblasts, through the secretion of interleukin-1 (IL-1) α. Using Affymetrix DNA microarrays, it was demonstrated that factors from keratinocytes regulate the expression of 69 genes important to wound healing. The regulation of 16 of these genes was confirmed by Northern blotting, and IL-1α from keratinocytes regulated all the 16 genes examined. IL-1-mediated CTGF gene regulation was further investigated. Both IL-1 isoforms, α and β, suppressed CTGF expression through an inhibition of CTGF promoter activity. Interestingly, transforming growth factor-β-stimulated Smad phosphorylation was not affected by IL-1. Finally, we hypothesized that CTGF is downregulated in burn wound by split-thickness skin grafting and that the expression of CTGF is suppressed during reepithelialization. The expression of CTGF protein was decreased in successfully skin-grafted wound areas, and increased in open, granulating burn wounds. Moreover, CTGF protein expression was absent beneath the migrating edge of reepithelialization ex vivo. In conclusion, we demonstrate that, in in vitro models, keratinocyte-derived IL-1α regulates the expression of CTGF and other genes with importance to wound healing. Furthermore, it is shown that CTGF expression is suppressed by epidermal wound coverage i burn wounds. These findings may have implications for the understanding of keratinocyte-fibroblast interplay during wound healing and in hypertrophic scar pathogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 50
Keyword
Surgery, conective tissue growth factor, interleukin-1, fibroblast, keratinocyte, wound healing, burns, Kirurgi
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-5840 (URN)91-554-6280-4 (ISBN)
Public defence
2005-06-03, Skoogsalen, Ingång79, Akademiska sjukhuset, Uppsala, 13:15
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Available from: 2005-05-13 Created: 2005-05-13Bibliographically approved

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Nowinski, DanielGerdin, Bengt

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