Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α: studies in two- and three dimensional in vitro models

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Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α : studies in two- and three dimensional in vitro models

Koskela von Sydow, Anita, 1979- (author): Örebro universitet,Institutionen för medicinska vetenskaper

Ivarsson, Mikael, Docent (thesis advisor): Örebro universitet,Institutionen för hälsovetenskaper

Bengtsson, Torbjörn, Professor (thesis advisor): Örebro universitet,Institutionen för medicinska vetenskaper

Törmä, Hans, Professor (opponent): Institutionen för medicinska vetenskaper, dermatologi och vereologi, Uppsala universitet

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ISBN 9789175291208
Örebro : Örebro university, 2016
English 83 s.
Series: Örebro Studies in Medicine, 1652-4063 ; 133

Related links:: https://oru.diva-por... (primary) (Raw object); show more...; https://oru.diva-por...; https://oru.diva-por...; https://urn.kb.se/re...; show less...

Doctoral thesis (other academic/artistic)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Andra medicinska och farmaceutiska grundvetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Other Basic Medicine (hsv//eng)

Keyword

Fibroblast
Keratinocyte
TGF-β
IL-1α
coculture
fibrosis CTGF/CNN 2
dermal
organotypic culture

Publication and Content Type

vet (subject category)
dok (subject category)

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