van Nieuwenhoven, FA, Hemmings, KE, Porter, KE et al. (1 more author) (2013) Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function. Matrix Biology, 32 (7-8). 399 - 406. ISSN 0945-053X
Abstract
During cardiac remodeling, cardiac fibroblasts (CF) are influenced by increased levels of interleukin-1α (IL-1α) and transforming growth factor-β1 (TGFβ1). The present study investigated the interaction between these two important cytokines on function of human CF and their differentiation to myofibroblasts (CMF). CF were isolated from human atrial appendage and exposed to IL-1α and/or TGFβ1 (both 0.1 ng/ml). mRNA expression levels of selected genes were determined after 6-24h by real-time RT-PCR, while protein levels were analyzed at 24-48 h by ELISA or western blot. Activation of canonical signaling pathways (NFκB, Smad3, p38 MAPK) was determined by western blotting. Differentiation to CMF was examined by collagen gel contraction assays. Exposure of CF to IL-1α alone enhanced levels of IL-6, IL-8, matrix metalloproteinase-3 (MMP3) and collagen III (COL3A1), but reduced the CMF markers α-smooth muscle actin (αSMA) and connective tissue growth factor (CTGF/CCN2). By contrast, TGFβ1 alone had minor effects on IL-6, IL-8 and MMP3 levels, but significantly increased levels of the CMF markers αSMA, CTGF, COL1A1 and COL3A1. Co-stimulation with both IL-1α and TGFβ1 increased MMP3 expression synergistically. Furthermore, while TGFβ1 had no effect on IL-1α-induced IL-6 or IL-8 levels, co-stimulation inhibited the TGFβ1-induced increase in αSMA and blocked the gel contraction caused by TGFβ1. Combining IL-1α and TGFβ1 had no apparent effect on their canonical signaling pathways. In conclusion, IL-1α and TGFβ1 act synergistically to stimulate MMP3 expression in CF. Moreover, IL-1α has a dominant inhibitory effect on the phenotypic switch of CF to CMF induced by TGFβ1.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | NOTICE: this is the author’s version of a work that was accepted for publication in Matrix Biology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Matrix Biology, 32 (7-8), 2013, 10.1016/j.matbio.2013.03.008 |
Keywords: | CF; CMF; COL1A1; COL3A1; CTGF; Cardiac fibroblasts; Cytokines; ECM; Extracellular matrix; Fibrosis; IL; Inflammation; MMP; Remodeling; TGFβ1; TNFα; alpha-smooth muscle actin; cardiac fibroblast; cardiac myofibroblast; collagen I; collagen III; connective tissue growth factor; extracellular matrix; interleukin; matrix metalloproteinase; transforming growth factor β1; tumor necrosis factor α; αSMA |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Genetics, Health and Therapeutics (LIGHT) > Academic Unit of Cardiovascular Medicine (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 19 Feb 2014 11:03 |
Last Modified: | 29 Mar 2018 09:09 |
Published Version: | http://dx.doi.org/10.1016/j.matbio.2013.03.008 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.matbio.2013.03.008 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:77824 |