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Lipopolysaccharide-Induced Expression of Matrix Metalloproteinases in Human Monocytes Is Suppressed by IFN- via Superinduction of ATF-3 and Suppression of AP-1¹

Hao H. Ho^*,, Taras T. Antoniv^*, Jong-Dae Ji^*, and Lionel B. Ivashkiv^2,*,

^* Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, Department of Pathology, New York University School of Medicine, New York, NY 10016; Division of Rheumatology, College of Medicine, Korea University, Seoul, Korea; and Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021

Matrix metalloproteinases (MMPs) are induced during inflammatory responses and are important for immune regulation, angiogenesis, wound healing, and tissue remodeling. Expression of MMPs needs to be tightly controlled to avoid excessive tissue damage. In this study, we investigated the regulation of MMP expression by inflammatory factors in primary human monocytes and macrophages. IFN-, which augments inflammatory cytokine production in response to macrophage-activating factors such as TLR ligands, instead broadly suppressed TLR-induced MMP expression. Inhibition of MMP expression was dependent on STAT1 and required de novo protein synthesis. IFN- strongly enhanced TLR-induced expression of the transcriptional repressor activating transcription factor (ATF-3) in a STAT1-dependent manner, which correlated with recruitment of ATF-3 to the endogenous MMP-1 promoter as detected by chromatin immunoprecipitation assays. RNA interference experiments further supported a role for ATF-3 in suppression of MMP-1 expression. In addition, IFN- suppressed DNA binding by AP-1 transcription factors that are known to promote MMP expression and a combination of supershift, RNA interference and overexpression experiments implicated AP-1 family member Fra-1 in the regulation of MMP-1 expression. These results define an IFN--mediated homeostatic loop that limits the potential for tissue damage associated with inflammation, and identify transcriptional factors that regulate MMP expression in myeloid cells in inflammatory settings.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (to L.B.I.).

² Address correspondence and reprint requests to Dr. Lionel B. Ivashkiv, Department of Medicine, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: ivashkivl{at}hss.edu

³ Abbreviations used in this paper: MMP, matrix metalloproteinase; ECM, extracellular matrix; ATF, activating transcription factor; PGE₂, prostaglandin E₂; RNAi, RNA interference; eGFP, enhanced GFP; shRNA, short hairpin RNA; siRNA, short interfering RNA duplex; ChIP, chromatin immunoprecipitation; GSK-3, glycogen synthase kinase 3.

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