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J Biol Chem, Vol. 274, Issue 43, 30919-30926, October 22, 1999

Interleukin-6 Increases Rat Metalloproteinase-13 Gene Expression through Stimulation of Activator Protein 1 Transcription Factor in Cultured Fibroblasts

José A. Solís-Herruzo^§, Richard A. Rippe, Laura W. Schrum, Paz de la Torre^§, Inmaculada García^§, John J. Jeffrey, Teresa Muñoz-Yagüe^§, and David A. Brenner

From the  Department of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599, the ^§ Department of Medicine, Gastroenterology, Hospital Universitario "12 de Octubre," Carretera de Andalucía 4,500, 28041 Madrid, Spain, and the  Division of Hematology, Department of Medicine, Albany Medical College, Albany, New York 12208

The role of IL-6 in collagen production and tissue remodeling is controversial. In Rat-1 fibroblasts, we measured the effect of IL-6 on matrix metalloproteinase-13 (MMP-13), c-jun, junB, and c-fos gene expression, binding of activator protein 1 (AP1) to DNA, amount of AP1 proteins, immunoreactive MMP-13 and TIMP-1 proteins, and Jun N-terminal kinase activity. We show that IL-6 increased MMP-13-mRNA and MMP-13 protein. These effects were exerted by acting on the AP1-binding site of the MMP-13 promoter, as shown by transfecting cells with reporter plasmids containing mutations in this element. Mobility shift assays demonstrated that IL-6 induced the DNA binding activity of AP1. This effect was accompanied by a marked increase in c-Jun, JunB, and c-Fos mRNA, as well as in c-Jun protein and its phosphorylated form. The latter is not due to increased Jun N-terminal kinase activity but to a decreased serine/threonine phosphatase activity. We conclude that IL-6 increases interstitial MMP-13 gene expression at the promoter level. This effect seems to be mediated by the induction of c-jun, junB, and c-fos gene expression, by the binding of AP1 to DNA, by increasing phosphorylated c-Jun, and by the inhibition of serine/threonine phosphatase activity. These effects of IL-6 might contribute to remodeling connective tissue.

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