Interferon-γ Differentially Regulates Monocyte Matrix Metalloproteinase-1 and -9 through Tumor Necrosis Factor-α and Caspase 8

• Published in: The Journal of biological chemistry 2003-11, Vol.278 (46), p.45406-45413
• Main Authors: Zhou, Min, Zhang, Yahong, Ardans, Jeanette A., Wahl, Larry M.
• Format: Article
• Language: English
• Subjects: Apoptosis; Blotting, Western; Caspase 8; Caspase 9; Caspases - metabolism; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Enzymologic; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; Interferon-gamma - metabolism; Matrix Metalloproteinase 1 - metabolism; Matrix Metalloproteinase 9 - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Models, Biological; Monocytes - metabolism; Monocytes - pathology; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Time Factors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M309075200

Tumor necrosis factor-α (TNFα) and granulocyte macrophage colony-stimulating factor (GM-CSF) individually enhance monocyte matrix metalloproteinase-9 (MMP-9) but induce MMP-1 only when added in combination. Because interferon-γ (IFNγ) is also found at inflammatory sites, we determined its effect on monocyte MMPs in the presence or absence of TNFα and GM-CSF. IFNγ alone did not stimulate monocyte MMP-9 or MMP-1; however, in the presence of GM-CSF it induced MMP-1 and enhanced MMP-1 stimulated by GM-CSF and TNFα. IFNγ induced MMP-1 in the presence of GM-CSF through the stimulation of TNFα production through a mechanism involving both p38 and ERK1/2 MAPKs, in which GM-CSF stimulated ERK1/2 whereas IFNγ activated p38. In support of this conclusion TNFα neutralizing antibody and antibodies against TNF receptor I and -II blocked the induction of MMP-1 by GM-CSF and IFNγ. In contrast to its effects on MMP-1, IFNγ inhibited TNFα-induced MMP-9 through a caspase 8-dependent pathway as demonstrated by the restoration of MMP-9 with caspase 8 inhibitors. Moreover, the phosphorylation of STAT1 by IFNγ was blocked by an inhibitor of caspase 8, indicating that STAT1 had a suppressive effect on MMP-9. Caspase 8-mediated phosphorylation of STAT1 through p38 MAPK as shown by the inhibition of IFNγ-induced phosphorylation of p38 by caspase 8 inhibitors. Activation of caspase 8 by IFNγ did not result in increased apoptosis. Thus IFNγ in the presence of GM-CSF and/or TNFα differentially regulates monocyte MMPs through induction of TNFα and a novel mechanism involving caspase 8 that is independent of apoptosis.