Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts.
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.
Brown
R Dale
RD
Division 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. Electronic address: Dale.Brown@uchsc.edu.
Jones
Gayle M
GM
Division 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.
Laird
Rebecca E
RE
Division 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.
Hudson
Paul
P
Division 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.
Long
Carlin S
CS
Division 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.
D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology*; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D053583:Interleukin-1beta; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases
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