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Cytokines regulate matrix metalloproteinase expression and cell migration in rat cardiac fibroblasts
Author(s) -
Brown R. Dale,
Jones Gayle M.,
Hudson Paul,
Laird Rebecca E.,
Mitchell M. Darren,
Long Carlin S.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1464-a
Subject(s) - matrix metalloproteinase , fibroblast , timp1 , extracellular matrix , cell migration , transforming growth factor , tumor necrosis factor alpha , cytokine , microbiology and biotechnology , mapk/erk pathway , chemistry , biology , cancer research , endocrinology , kinase , immunology , cell , gene expression , in vitro , biochemistry , gene
Cardiac fibroblasts migrate into zones of myocardial injury, where they contribute importantly to extracellular matrix remodeling through expression of matrix metalloproteinases (MMPs). We investigated the relationship between cytokine stimulated release of MMPs and cell migration in cultured adult rat cardiac fibroblasts. Release of MMPs 2, 3, 9, and TIMP1 into culture supernatants was determined by gel zymography and immunoblotting with quantitative densitometry. Fibroblast migration was measured in modified Boyden chambers. Interleukin‐1β (IL‐1) increased MMPs 2, 3, and 9, and TIMP1. Tumor necrosis factor‐α (TNFα) and interferon‐γ (IFNγ) had lesser effects alone and modestly augmented IL‐1 response. Transforming growth factor‐β 1 (TGFβ 1) attenuated all the responses to IL‐1. IL‐1 was also the most robust stimulus of fibroblast migration. The combination of IL‐1 plus TNFα substantially enhanced migration, whereas IFNγ and TGFβ strongly inhibited the migratory response to IL‐1. Moreover, the pan‐selective MMP inhibitor GM 6001 abolished IL‐1 stimulated migration. Selective pharmacologic inhibition of ERK, JNK, and p38 MAP kinases demonstrated heterogeneities in the IL‐1 regulation of individual MMPs. In conclusion, increased MMP expression associates with cardiac fibroblast migration but does not independently determine the migratory response, whereas MMP inhibition appears sufficient to block migration. Cardiac fibroblast migration and remodeling reflect combinatorial cytokine interactions in the injured myocardium. Supported by NIH (HL59428).