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Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts

R Dale Brown1, Gayle M Jones1, Rebecca E Laird1

  • 1Division of Cardiology, University of Colorado at Denver and Health Sciences Center, and Denver Health Medical Center, B-139, 4200 E. 9th Avenue, Denver, CO 80262, USA.

Biochemical and Biophysical Research Communications
|August 21, 2007
PubMed

Insights

Cytokines like Interleukin-1beta stimulate cardiac fibroblast migration and matrix metalloproteinase (MMP) release. MMP inhibition blocks this migration, suggesting a role in cardiac repair.

Area of Science:

  • Cardiovascular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Cytokines play a crucial role in tissue repair and remodeling.
  • Matrix metalloproteinases (MMPs) are key enzymes involved in extracellular matrix degradation.
  • Cardiac fibroblasts are important cells in myocardial structure and response to injury.

Purpose of the Study:

  • To investigate the relationship between cytokine-induced matrix metalloproteinase (MMP) release and cell migration in adult rat cardiac fibroblasts.
  • To elucidate the specific roles of Interleukin-1beta (IL-1beta), Tumor Necrosis Factor-alpha (TNFalpha), and Transforming Growth Factor-beta1 (TGFbeta1) in regulating MMPs and fibroblast migration.
  • To determine the involvement of MMPs in cytokine-directed cardiac fibroblast migration.

Main Methods:

  • Adult rat cardiac fibroblasts were treated with various cytokines (IL-1beta, TNFalpha, TGFbeta1).
  • MMP and TIMP-1 release was quantified using immunoblotting and gel zymography.
  • Cell migration was assessed using Boyden chamber assays.
  • Pharmacologic inhibitors of MMPs and specific MAP kinase pathways (ERK, JNK, p38) were employed.

Main Results:

  • IL-1beta significantly increased the release of MMP-2, MMP-3, MMP-9, and TIMP-1.
  • TNFalpha augmented IL-1beta-induced MMP-9 release, while TGFbeta1 attenuated IL-1beta's effects on MMPs.
  • IL-1beta was a potent stimulator of cardiac fibroblast migration, further enhanced by TNFalpha but inhibited by TGFbeta1.
  • A broad-spectrum MMP inhibitor (GM 6001) blocked IL-1beta-stimulated migration.
  • Inhibitors of ERK, JNK, and p38 MAP kinase pathways differentially affected IL-1beta-induced MMP regulation.

Conclusions:

  • Cytokine stimulation, particularly by IL-1beta, drives cardiac fibroblast migration through the release of MMPs.
  • MMPs are critical mediators of cytokine-induced cardiac fibroblast migration.
  • These findings highlight the potential role of MMP activity in the cytokine-directed remodeling of injured myocardium.

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