Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro

Circ Res. 2000 Jun 23;86(12):1259-65. doi: 10.1161/01.res.86.12.1259.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Collagen / antagonists & inhibitors*
  • Collagen / biosynthesis
  • Collagen / genetics
  • Fibroblasts / metabolism*
  • Inflammation Mediators / pharmacology
  • Interleukin-1 / pharmacology*
  • Matrix Metalloproteinases / genetics
  • Matrix Metalloproteinases / metabolism*
  • Myocardium / metabolism*
  • Nitric Oxide / physiology
  • RNA, Messenger / antagonists & inhibitors
  • Rats
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Inflammation Mediators
  • Interleukin-1
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Collagen
  • Matrix Metalloproteinases