Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts

Biochem Biophys Res Commun. 2007 Oct 12;362(1):200-205. doi: 10.1016/j.bbrc.2007.08.003. Epub 2007 Aug 9.

Abstract

We sought to define the relationship between cytokine stimulated release of matrix metalloproteinases (MMPs) and cell migration using adult rat cardiac fibroblasts. Interleukin-1beta (IL-1beta) increased release of MMP-2, -3, and -9, and TIMP-1, by 3-6-fold, measured by immunoblotting and gel zymography. Tumor necrosis factor-alpha (TNFalpha) augmented IL-1beta stimulated release of MMP-9, but not MMP-2 or -3. Transforming growth factor-beta1 (TGFbeta1) attenuated all the responses to IL-1beta. IL-1beta was also the most robust stimulus of adult rat cardiac fibroblast migration, measured in Boyden chamber assays. The combination of IL-1beta plus TNFalpha substantially enhanced migration, whereas TGFbeta1 strongly inhibited the migratory response to IL-1beta. The pan-selective MMP inhibitor GM 6001 effectively blocked IL-1beta stimulated migration. Pharmacologic inhibitors selective for ERK, JNK, and p38 MAP kinase pathways inhibited the IL-1beta regulation of individual MMPs. Increased MMP activity associated with migration of cardiac fibroblasts may be important determinants of cytokine-directed remodeling of injured myocardium.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Movement
  • Cytokines / metabolism*
  • Fibroblasts / cytology*
  • Gene Expression Regulation*
  • Heart / physiology
  • Interleukin-1beta / metabolism
  • MAP Kinase Signaling System
  • Matrix Metalloproteinases / metabolism*
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta1 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cytokines
  • Interleukin-1beta
  • Transforming Growth Factor beta1
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinases