title: Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro.
abstract: We tested the hypothesis that the inflammatory cytokines can regulate fibroblast extracellular matrix metabolism. Neonatal and adult rat cardiac fibroblasts cultures in vitro were exposed to interleukin (IL)-1beta (4 ng/mL), tumor necrosis factor-alpha (TNF-alpha; 100 ng/mL), IL-6 (10 ng/mL), or interferon-gamma (IFN-gamma; 500 U/mL) for 24 hours. IL-1beta, and to a lesser extent TNF-alpha, decreased collagen synthesis, which was measured as collagenase-sensitive [(3)H]proline incorporation, but had no effect on cell number or total protein synthesis. IL-1beta decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha1(III) mRNA, but increased the expression of procollagen alpha(1)(IV), alpha(2)(IV), and fibronectin mRNA, indicating a selective transcriptional downregulation of fibrillar collagen synthesis. IL-1beta and TNF-alpha each increased total matrix metalloproteinase (MMP) activity as measured by in-gel zymography, causing specific increases in the bands corresponding to MMP-13, MMP-2, and MMP-9. IL-1beta increased the expression of proMMP-2 and proMMP-3 mRNA, suggesting that increased metalloproteinase activity is due, at least in part, to increased transcription. The effects of IL-1beta were not dependent on NO production. Thus, IL-1beta and TNF-alpha decrease collagen synthesis and activate MMPs that degrade collagen. These observations suggest that IL-1beta and TNF-alpha may contribute to ventricular dilation and myocardial failure by promoting the remodeling of interstitial collagen.
authors.affiliation: Myocardial Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA. USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Siwik
authors.forename: D L
authors.initials: DL
authors.lastname: Chang
authors.forename: W S
authors.initials: WS
authors.lastname: Colucci
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism*; D018836:Inflammation Mediators / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018836:Inflammation Mediators; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003094:Collagen; D020782:Matrix Metalloproteinases