© 2000 American Heart Association, Inc.
Molecular Medicine |
Interleukin-1ß and Tumor Necrosis Factor-
Decrease Collagen Synthesis and Increase Matrix Metalloproteinase Activity in Cardiac Fibroblasts In Vitro
From the Myocardial Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, and Cardiovascular Division, Boston University Medical Center, Boston, Mass.
Correspondence to Wilson S. Colucci, MD, Cardiovascular Division, Boston University Medical Center, 88 East Newton St, Boston, MA 02118. E-mail wilson.colucci{at}bmc.org
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)–1ß (4 ng/mL), tumor necrosis factor-
(TNF-; 100 ng/mL),
IL-6 (10 ng/mL), or interferon-
(IFN-; 500 U/mL) for 24 hours.
IL-1ß, and to a lesser extent TNF-, decreased collagen synthesis,
which was measured as collagenase-sensitive
[3H]proline incorporation, but had no effect on cell
number or total protein synthesis. IL-1ß decreased the expression of
procollagen 1(I), 2(I), and 1(III)
mRNA, but increased the expression of procollagen 1(IV),
2(IV), and fibronectin mRNA, indicating a selective
transcriptional downregulation of fibrillar collagen synthesis. IL-1ß
and TNF- 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-1ß
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-1ß were not dependent on
NO production. Thus, IL-1ß and TNF- decrease collagen
synthesis and activate MMPs that degrade collagen. These
observations suggest that IL-1ß and TNF- may contribute to
ventricular dilation and myocardial failure by promoting
the remodeling of interstitial collagen.
Key Words: inflammatory cytokines • interleukin-1ß • tumor necrosis factor- • collagen • matrix metalloproteinase
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