title: IL-1α Counteract TGF-β Regulated Genes and Pathways in Human Fibroblasts.
abstract: 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. J. Cell. Biochem. 117: 1622-1632, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Medicine and Health, Örebro University, Örebro, Sweden.|Department of Clinical Research Laboratory, University Hospital, Örebro, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Koskela von Sydow
authors.affiliation: Faculty of Medicine and Health, Örebro University, Örebro, Sweden.|Department of Plastic and Reconstructive Surgery, University Hospital, Örebro, Sweden.
authors.forename: Chris
authors.initials: C
authors.lastname: Janbaz
authors.affiliation: Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kardeby
authors.affiliation: Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Dirk
authors.initials: D
authors.lastname: Repsilber
authors.affiliation: Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Ivarsson
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C508584:IL1A protein, human; D053582:Interleukin-1alpha; D016212:Transforming Growth Factor beta
keywords: CONNECTIVE TISSUE GROWTH FACTOR; FIBROBLAST; FIBROSIS AND INGENUITY PATHWAY ANALYSIS; INTERFERON; INTERLEUKIN-1; TRANSFORMING GROWTH FACTOR-BETA