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IL-1α counteracts TGF-β regulated protein expression in human dermal fibroblasts
Örebro universitet, Institutionen för hälsovetenskaper.ORCID-id: 0000-0001-8304-2772
Department of Plastic and Reconstructive Surgery Clinic, School of Medical Science, Örebro University SE 70182, Örebro, Sweden.
Örebro universitet, Institutionen för hälsovetenskaper. Department of Internal Medicine, Division of Gastroenterology.
Örebro universitet, Institutionen för hälsovetenskaper.
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
URN: urn:nbn:se:oru:diva-48464OAI: oai:DiVA.org:oru-48464DiVA, id: diva2:905461
Tillgänglig från: 2016-02-22 Skapad: 2016-02-22 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
Ingår i avhandling
1. Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α: studies in two- and three dimensional in vitro models
Öppna denna publikation i ny flik eller fönster >>Regulation of fibroblast activity by keratinocytes, TGF-β and IL-1α: studies in two- and three dimensional in vitro models
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Örebro: Örebro university, 2016. s. 83
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 133
Nyckelord
Fibroblast, Keratinocyte, TGF-β, IL-1α, coculture, fibrosis CTGF/CNN 2, dermal, organotypic culture
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
urn:nbn:se:oru:diva-48225 (URN)978-91-7529-120-8 (ISBN)
Disputation
2016-03-18, Universitetssjukhuset, Wilandersalen, Södra Grev Rosengatan, Örebro, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-02-12 Skapad: 2016-02-12 Senast uppdaterad: 2018-01-10Bibliografiskt granskad

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Koskela von Sydow, AnitaBergemalm, DanielIvarsson, Mikael

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