AP-1 Superinduction of ATF-3 and Suppression of via ³ Monocytes

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  • of April 12, 2018.This information is current as AP-1

    Superinduction of ATF-3 and Suppression of viaMonocytes Is Suppressed by IFN-

    Matrix Metalloproteinases in Human Lipopolysaccharide-Induced Expression of

    IvashkivHao H. Ho, Taras T. Antoniv, Jong-Dae Ji and Lionel B.

    http://www.jimmunol.org/content/181/7/5089doi: 10.4049/jimmunol.181.7.5089

    2008; 181:5089-5097; ;J Immunol

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  • Lipopolysaccharide-Induced Expression of MatrixMetalloproteinases in Human Monocytes Is Suppressedby IFN- via Superinduction of ATF-3 and Suppressionof AP-11

    Hao H. Ho,* Taras T. Antoniv,* Jong-Dae Ji,* and Lionel B. Ivashkiv2*

    Matrix metalloproteinases (MMPs) are induced during inflammatory responses and are important for immune regulation, an-giogenesis, wound healing, and tissue remodeling. Expression of MMPs needs to be tightly controlled to avoid excessive tissuedamage. In this study, we investigated the regulation of MMP expression by inflammatory factors in primary human monocytesand macrophages. IFN-, which augments inflammatory cytokine production in response to macrophage-activating factors suchas TLR ligands, instead broadly suppressed TLR-induced MMP expression. Inhibition of MMP expression was dependent onSTAT1 and required de novo protein synthesis. IFN- strongly enhanced TLR-induced expression of the transcriptional repressoractivating transcription factor (ATF-3) in a STAT1-dependent manner, which correlated with recruitment of ATF-3 to theendogenous MMP-1 promoter as detected by chromatin immunoprecipitation assays. RNA interference experiments furthersupported a role for ATF-3 in suppression of MMP-1 expression. In addition, IFN- suppressed DNA binding by AP-1 tran-scription factors that are known to promote MMP expression and a combination of supershift, RNA interference and overex-pression experiments implicated AP-1 family member Fra-1 in the regulation of MMP-1 expression. These results define anIFN--mediated homeostatic loop that limits the potential for tissue damage associated with inflammation, and identify tran-scriptional factors that regulate MMP expression in myeloid cells in inflammatory settings. The Journal of Immunology, 2008,181: 50895097.

    S ince the discovery of the first matrix metalloproteinase(MMP)3 in the regressing tadpole tail by Gross andLapiere in 1962 (1), the list of functions assigned to var-ious MMPs has been expanding rapidly. MMPs were initiallythought to be a group of enzymes with the sole function of regu-lating extracellular matrix (ECM) composition. However, intenseresearch in recent years has shown that ECM degradation is not thesole and possibly not the main function of these proteinases. In-deed, plenty of evidence supports roles of MMPs in physiologicalprocesses such as embryogenesis and wound healing/tissue remod-eling and also in pathological processes that include arthritis, pul-monary diseases, cardiovascular ailments, and cancer (27). In ad-dition to ECM remodeling MMPs regulate signal transduction andgrowth factor function, and recent findings also indicate that

    MMPs are immunoregulators by acting on inflammatory cyto-kines, chemokines, and other immune proteins (818).

    Not surprisingly, the activity of MMPs is tightly regulated atmultiple levels that include gene expression, compartmentaliza-tion, proenzyme activation, and enzyme inactivation, catabolism,and clearance (3, 18). Expression of many MMPs is normally lowor absent in healthy tissues, but they are induced when tissue re-modeling is required, during inflammation, and in disease statessuch as rheumatoid arthritis and cancer in which high levels ofMMPs may signify a poor prognosis in human patients (19). MMPgene expression is mainly regulated at the transcriptional level inresponse to hormones, growth factors, cytokines, and cell-cell/cell-matrix interactions (3, 5, 20). Though the expression of MMPs indiseased states is intended to restore normal homeostasis, in a set-ting such as inflammation the up-regulation of various MMPs maylead to more damage than repair (5).

    Rheumatoid arthritis and atherosclerosis are disorders of chronicinflammation, and macrophages are central players in both of thesepathological conditions (2123). Though the importance of mac-rophage-derived MMPs in cartilage and/or bone destruction inrheumatoid arthritis has not been fully elucidated, their role inatherosclerosis progression is well documented (21, 24). In ath-erosclerosis, macrophages accumulate lipid to form foam cells.The accumulation of foam cells in an atheroma is reversible anddoes not in itself cause clinical consequences. However, the se-cretion of MMPs by the atheromatous plaque-associated macro-phages can cause plaque destabilization, leading to acute coronaryevents with high morbidity and mortality (22, 23, 25). Among theMMPs produced by macrophages, MMP-1 (collagenase-1),MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-7 (matri-lysin-1), MMP-9 (gelatinase B), MMP-12 (metalloelastase), and

    *Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital forSpecial Surgery, Department of Pathology, New York University School of Medi-cine, New York, NY 10016; Division of Rheumatology, College of Medicine, KoreaUniversity, Seoul, Korea; and Graduate Program in Immunology, Weill GraduateSchool of Medical Sciences of Cornell University, New York, NY 10021

    Received for publication September 11, 2007. Accepted for publication July 23, 2008.

    The costs of publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked advertisement in accordancewith 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, Departmentof Medicine, Hospital for Special Surgery, 535 East 70th Street, New York, NY10021. E-mail address: ivashkivl@hss.edu3 Abbreviations used in this paper: MMP, matrix metalloproteinase; ECM, extracel-lular matrix; ATF, activating transcription factor; PGE2, prostaglandin E2; RNAi,RNA interference; eGFP, enhanced GFP; shRNA, short hairpin RNA; siRNA, shortinterfering RNA duplex; ChIP, chromatin immunoprecipitation; GSK-3, glycogensynthase kinase 3.

    Copyright 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00

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  • MMP-13 (metalloproteinase-13) have been associated with athero-sclerotic plaque instability and rupture (22, 23, 2527). Therefore,understanding the regulation of MMPs in inflammatory conditionsis crucial in formulating a therapeutic intervention to prevent dis-ease progression.

    Most studies on regulation of MMP expression have been per-formed using fibroblasts, chondrocytes, osteoblasts, and cell linessuch as HEK293, HeLa and NIH-3T3 cells (7, 2845), with veryfew studies using monocytes/macrophages (4648). BecauseMMP expression is regulated differently in the various cell typesand cell lines studied to date, we were interested in understandingMMP regulation in primary human monocytes and macrophagesthat are relevant for inflammatory diseases, and defining mecha-nisms that inhibit MMP expression. In this study, we found that inprimary human macrophages IFN- globally inhibits induction ofMMPs by Toll-like receptors, innate immune receptors that play akey role in activation of macrophages by microbial products andendogenous ligands that include ECM degradation products. Fur-ther analysis of the regulation of MMP-1 showed that the mech-anism of IFN--mediated inhibition involves induction of the tran-scriptional repressor activating transcription factor (ATF)-3 andsuppression of DNA binding by AP-1 proteins. Prostaglandin E2(PGE2) also down-regulated LPS-induced MMP-1 expression, andsuppression by PGE2 and IFN- converged on inhibition of AP-1proteins and regulation of