Lipopolysaccharide-induced expression of matrix metalloproteinases in human monocytes is suppressed by IFN-gamma via superinduction of ATF-3 and suppression of AP-1.
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-gamma, 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-gamma 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-gamma 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-gamma-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.
Ho
Hao H
HH
Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, New York University School of Medicine, New York, NY 10016, USA.
Antoniv
Taras T
TT
Ji
Jong-Dae
JD
Ivashkiv
Lionel B
LB
D051700:Activating Transcription Factor 3 / Q000096:biosynthesis* / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D025461:Feedback, Physiological / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D018836:Inflammation Mediators / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000099169:Fos-Related Antigen 1
D051700:Activating Transcription Factor 3; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D020781:Matrix Metalloproteinase 1; D061965:Matrix Metalloproteinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D012097:Repressor Proteins; D013755:Tetradecanoylphorbol Acetate; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C490449:ATF3 protein, human; C522360:MMP1 protein, human
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