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), a key cell type involved in the regulation of myocardial remodelling. We used a focused RT-PCR microarray to investigate the effects of IL-1 on expression of 41 ECM genes in CMF cultured from different patients, and explored the regulatory role of the p38 MAPK signalling pathway. IL-1 (10 ng/ml, 6 h) had only a minimal effect on mRNA expression of structural ECM proteins, including collagens, laminins, fibronectin and vitronectin. However, IL-1 induced marked increases in expression of several ECM proteases, including matrix metalloproteinases MMP-1 (collagenase-1), MMP-3 (stromelysin-1), MMP-9 (gelatinase-B) and MMP-10 (stromelysin-2). Conversely, IL-1 reduced mRNA expression of ADAMTS-1, a metalloproteinase that suppresses neovascularisation. IL-1 stimulated a small increase in expression of tissue inhibitor of metalloproteinases (TIMP)-1, but not TIMP-2. Data for MMPs 1, 2, 3, 9 and 10 and ADAMTS-1 were confirmed by quantitative real-time RT-PCR. IL-1 strongly activated the p38 MAPK pathway in human CMF, as determined by immunoblotting with phospho-specific antibodies. A p38 MAPK inhibitor (SB203580) reduced IL-1-induced mRNA expression of MMP-3, but did not affect expression of any of the other MMPs studied. SB203580 also markedly reduced ADAMTS-1 mRNA expression.
In summary, IL-1 induces a distinct pattern of ECM protease expression in human CMF, in part regulated by p38 MAPK, affirming the key role of IL-1 and CMF in postinfarction cardiac remodelling.
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Funding Funded by a British Heart Foundation project grant.
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