Classical macrophage activation up-regulates several matrix metalloproteinases through mitogen activated protein kinases and nuclear factor-κB

Remodelling of the extracellular matrix (ECM) and cell surface by matrix metalloproteinases (MMPs) is an important function of monocytes and macrophages. Recent work has emphasised the diverse roles of classically and alternatively activated macrophages but the consequent regulation of MMPs and thei...

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Bibliographic Details
Published in:PloS one 2012-08, Vol.7 (8), p.e42507
Main Authors: Huang, Wei-Chun, Sala-Newby, Graciela B, Susana, Angela, Johnson, Jason L, Newby, Andrew C
Format: Article
Language:English
Subjects:
Arteriosclerosis
Arthritis
Atherosclerosis
Atherosclerosis - enzymology
Atherosclerosis - pathology
Biology
Blood & organ donations
CD16 antigen
Cell activation
Cell Adhesion - drug effects
Cell surface
Chromones - pharmacology
Collagen
Collagenase
Cytokines
Enzyme Activation - drug effects
Enzyme inhibitors
Enzymes
Ethics
Extracellular matrix
Gelatinase A
Gene expression
Gene Expression Regulation, Enzymologic - drug effects
Heart
Humans
Inflammation
Interferon-gamma - pharmacology
Interleukin 1
Interleukin-1 - pharmacology
Interstitial collagenase
Janus kinase
Janus Kinase 2 - antagonists & inhibitors
Janus Kinase 2 - metabolism
Kinases
Lipopolysaccharides
Lipopolysaccharides - pharmacology
Macrophage Activation - drug effects
Macrophages
Macrophages - cytology
Macrophages - drug effects
Macrophages - enzymology
Matrix metalloproteinase
Matrix metalloproteinases
Matrix Metalloproteinases - genetics
Matrix Metalloproteinases - metabolism
Medicine
Mitogen-Activated Protein Kinases - genetics
Mitogen-Activated Protein Kinases - metabolism
Monocytes
Monocytes - cytology
Monocytes - drug effects
Morpholines - pharmacology
mRNA
NF-kappa B - metabolism
Phenotype
Phosphatidylinositol 3-Kinases - metabolism
Plaques
Proteins
R&D
Receptors, IgG - metabolism
Research & development
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Signal transduction
Signaling
STAT1 Transcription Factor - metabolism
Steady state
Thiophenes - pharmacology
Tissue inhibitor of metalloproteinase 3
Tissue Inhibitor of Metalloproteinases - genetics
Tissue Inhibitor of Metalloproteinases - metabolism
Tumor Necrosis Factor-alpha - pharmacology
Tumor necrosis factor-α
Up-Regulation - drug effects
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Summary:Remodelling of the extracellular matrix (ECM) and cell surface by matrix metalloproteinases (MMPs) is an important function of monocytes and macrophages. Recent work has emphasised the diverse roles of classically and alternatively activated macrophages but the consequent regulation of MMPs and their inhibitors has not been studied comprehensively. Classical activation of macrophages derived in vitro from un-fractionated CD16(+/-) or negatively-selected CD16(-) macrophages up-regulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. Bacterial lipopolysaccharide, IL-1 and TNFα were more effective than interferonγ except for the effects on MMP-25, and TIMP-3. By contrast, alternative activation decreased MMP-2, -8 and -19 but increased MMP -11, -12, -25 and TIMP-3 steady-state mRNA levels. Up-regulation of MMPs during classical activation depended on mitogen activated protein kinases, phosphoinositide-3-kinase and inhibitor of κB kinase-2. Effects of interferonγ depended on janus kinase-2. Where investigated, similar effects were seen on protein concentrations and collagenase activity. Moreover, activity of MMP-1 and -10 co-localised with markers of classical activation in human atherosclerotic plaques in vivo. In conclusion, classical macrophage activation selectively up-regulates several MMPs in vitro and in vivo and down-regulates TIMP-3, whereas alternative activation up-regulates a distinct group of MMPs and TIMP-3. The signalling pathways defined here suggest targets for selective modulation of MMP activity.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0042507