title: Modulatory effect of interleukin-1α on expression of structural matrix proteins, MMPs and TIMPs in human cardiac myofibroblasts: role of p38 MAP kinase.
abstract: The proinflammatory cytokine interleukin-1 (IL-1) elicits catabolic effects on the myocardial extracellular matrix (ECM) early after myocardial infarction but there is little understanding of its direct effects on cardiac myofibroblasts (CMF), or the role of p38 mitogen-activated protein kinase (MAPK). We used a focused RT-PCR microarray to investigate the effects of IL-1α on expression of 41 ECM genes in CMF cultured from different patients, and explored regulation by p38 MAPK. IL-1α (10 ng/ml, 6h) had minimal effect on mRNA expression of structural ECM proteins, including collagens, laminins, fibronectin and vitronectin. However, it induced marked increases in expression of specific ECM proteases, including matrix metalloproteinases MMP-1 (collagenase-1), MMP-3 (stromelysin-1), MMP-9 (gelatinase-B) and MMP-10 (stromelysin-2). Conversely, IL-1α reduced mRNA and protein expression of ADAMTS1, a metalloproteinase that suppresses neovascularization. IL-1α increased expression of TIMP-1 slightly, but not TIMP-2. Data for MMP-1, MMP-2, MMP-3, MMP-9, MMP-10 and ADAMTS1 were confirmed by quantitative real-time RT-PCR. Tumor necrosis factor-alpha (TNFα), another important myocardial proinflammatory cytokine, did not alter expression of these metalloproteinases. IL-1α strongly activated the p38 MAPK pathway in human CMF. Pharmacological inhibitors of p38-α/β (SB203580) or p38-α/β/γ/δ (BIRB-0796) reduced MMP-3 and ADAMTS1 mRNA expression, but neither inhibitor affected MMP-9 levels. MMP-1 and MMP-10 expression were inhibited by BIRB-0796 but not SB203580, suggesting roles for p38-γ/δ. In summary, IL-1α induces a distinct pattern of ECM protein and protease expression in human CMF, in part regulated by distinct p38 MAPK subtypes, affirming the key role of IL-1α and CMF in post-infarction cardiac remodeling.
authors.affiliation: Division of Cardiovascular and Neuronal Remodelling, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK. n.a.turner@leeds.ac.uk
authors.forename: Neil A
authors.initials: NA
authors.lastname: Turner
authors.forename: Philip
authors.initials: P
authors.lastname: Warburton
authors.forename: David J
authors.initials: DJ
authors.lastname: O'Regan
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ball
authors.forename: Karen E
authors.initials: KE
authors.lastname: Porter
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071097:ADAMTS1 Protein; D003094:Collagen / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D053582:Interleukin-1alpha / Q000494:pharmacology*; D007700:Kinetics; D007797:Laminin / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics*; D018832:Molecular Chaperones; D009206:Myocardium / Q000166:cytology; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D053582:Interleukin-1alpha; D007797:Laminin; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human; D020782:Matrix Metalloproteinases