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-1 beta (IL-1 beta) 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 (TNF alpha) augmented IL-1 beta stimulated release of MMP-9, but not MMP-2 or -3. Transforming growth factor-beta 1 (TGF beta 1) attenuated all the responses to IL-1 beta. IL-1 beta was also the most robust stimulus of adult rat cardiac fibroblast migration, measured in Boyden chamber assays. The combination of IL-1 beta plus TNF alpha substantially enhanced migration, whereas TGF beta 1 strongly inhibited the migratory response to IL-1 beta. The pan-selective NIMP inhibitor GM 6001 effectively blocked IL-1 beta stimulated migration. Pharmacologic inhibitors selective for ERK, JNK, and p38 MAP kinase pathways inhibited the IL-1 beta regulation of individual MMPs. Increased NIMP activity associated with migration of cardiac fibroblasts may be important determinants of cytokine-directed remodeling of injured myocardium. (C) 2007 Elsevier Inc. All rights reserved.