title: Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts.
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.
authors: 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.
authors: R Dale
authors: RD
authors: Brown
authors: 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.
authors: Gayle M
authors: GM
authors: Jones
authors: 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.
authors: Rebecca E
authors: RE
authors: Laird
authors: 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.
authors: Paul
authors: P
authors: Hudson
authors: 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.
authors: Carlin S
authors: CS
authors: Long
mesh_terms: 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
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases
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