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.