oru.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts
Department of Clinical Research Laboratory, Örebro University Hospital, Örebro, Sweden.ORCID-id: 0000-0001-8304-2772
Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Plastic and Reconstructive Surgery, Örebro University Hospital, Örebro, Sweden .
Örebro universitet, Institutionen för medicinska vetenskaper.ORCID-id: 0000-0002-5025-9454
Örebro universitet, Institutionen för medicinska vetenskaper.ORCID-id: 0000-0002-7173-5579
Visa övriga samt affilieringar
2016 (Engelska)Ingår i: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 117, nr 7, s. 1622-1632Artikel i tidskrift (Refereegranskat) Published
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. We previously showed that interleukin-1 (IL-1α) counteracts TGF-β-stimulated CTGF mRNA and protein expression in these cells. The aim of this study was to explore the effects of IL-1α on further genes and pathways in TGF-β regulated fibroblasts. Transcriptional microarray and multiple comparison analysis showed that the antagonizing effects of IL-1α was much more prominent than the synergistic effects, both with respect to number of genes and extent of changes in gene expression. Moreover, comparing canonical pathways by gene set enrichment analysis and the Ingenuity Pathway Analysis tool revealed that IL-1α counteracted TGF-β in the top six most confident pathways regulated by both cytokines. Interferon and IL-1 signaling, as well as two pathways involved in apoptosis signaling were suppressed by TGF-β and activated by IL-1α. Pathways involving actin remodeling and focal adhesion dynamics were activated by TGF-β and suppressed by IL-1α. Analyzing upstream regulators in part corroborate the comparison of canonical pathways and added cell cycle regulators as another functional group regulated by IL-1α. Finally, gene set enrichment analysis of fibrosis-related genes indicated that IL-1 moderately counteracts the collective effect of TGF-β on these genes. Microarray results were validated by qPCR. Taken together, the results indicate prominent antagonistic effects of IL-1α on TGF-β regulated interferon signaling, as well as on a wide variety of other genes and pathways in fibroblasts. This article is protected by copyright. All rights reserved.

Ort, förlag, år, upplaga, sidor
Hoboken, USA: Wiley-Blackwell, 2016. Vol. 117, nr 7, s. 1622-1632
Nyckelord [en]
Connective tissue growth factor, transforming growth factor-beta, interleukin-1, interferon, fibroblast, fibrosis and ingenuity pathway analysis
Nationell ämneskategori
Annan medicinsk grundvetenskap Cellbiologi Biokemi och molekylärbiologi
Forskningsämne
Cellforskning
Identifikatorer
URN: urn:nbn:se:oru:diva-48463DOI: 10.1002/jcb.25455ISI: 000375916800014PubMedID: 26629874Scopus ID: 2-s2.0-84964773875OAI: oai:DiVA.org:oru-48463DiVA, id: diva2:905457
Anmärkning

Funding Agencies:

Örebro County Council Research Committee of the Örebro University Hospital OLL-550071

Nyckelfonden AE56340

Tillgänglig från: 2016-02-22 Skapad: 2016-02-22 Senast uppdaterad: 2019-03-26Bibliografiskt 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

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltextPubMedScopus

Personposter BETA

Koskela von Sydow, AnitaKardeby, CarolineRepsilber, DirkIvarsson, Mikael

Sök vidare i DiVA

Av författaren/redaktören
Koskela von Sydow, AnitaKardeby, CarolineRepsilber, DirkIvarsson, Mikael
Av organisationen
Institutionen för medicinska vetenskaperInstitutionen för hälsovetenskaper
I samma tidskrift
Journal of Cellular Biochemistry
Annan medicinsk grundvetenskapCellbiologiBiokemi och molekylärbiologi

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 616 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf