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Interferon-gamma differentially regulates monocyte matrix metalloproteinase-1 and -9 through tumor necrosis
Min Zhou1, Yahong Zhang, Jeanette A Ardans
1Immunopathology Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
Tumor necrosis factor-alpha (TNFalpha) 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-gamma (IFNgamma) is also found at inflammatory sites, we determined its effect on monocyte MMPs in the presence or absence of TNFalpha and GM-CSF. IFNgamma 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 TNFalpha. IFNgamma induced MMP-1 in the presence of GM-CSF through the stimulation of TNFalpha production through a mechanism involving both p38 and ERK1/2 MAPKs, in which GM-CSF stimulated ERK1/2 whereas IFNgamma activated p38. In support of this conclusion TNFalpha neutralizing antibody and antibodies against TNF receptor I and -II blocked the induction of MMP-1 by GM-CSF and IFNgamma. In contrast to its effects on MMP-1, IFNgamma inhibited TNFalpha-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 IFNgamma 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 IFNgamma-induced phosphorylation of p38 by caspase 8 inhibitors. Activation of caspase 8 by IFNgamma did not result in increased apoptosis. Thus IFNgamma in the presence of GM-CSF and/or TNFalpha differentially regulates monocyte MMPs through induction of TNFalpha and a novel mechanism involving caspase 8 that is independent of apoptosis.
Insights
Interferon-gamma (IFNgamma) combined with other factors differentially regulates monocyte matrix metalloproteinases (MMPs). IFNgamma induces MMP-1 via TNFalpha and caspase 8, while inhibiting MMP-9 through a caspase 8-dependent pathway.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Tumor necrosis factor-alpha (TNFalpha) and granulocyte macrophage colony-stimulating factor (GM-CSF) individually enhance monocyte matrix metalloproteinase-9 (MMP-9) but induce MMP-1 only when combined.
- Interferon-gamma (IFNgamma) is present at inflammatory sites, necessitating an understanding of its role in monocyte MMP regulation.
Purpose of the Study:
- To investigate the effect of IFNgamma on monocyte MMP-1 and MMP-9 production, both alone and in combination with TNFalpha and GM-CSF.
- To elucidate the signaling pathways involved in IFNgamma-mediated regulation of monocyte MMPs.
Main Methods:
- Monocyte cultures were treated with combinations of TNFalpha, GM-CSF, and IFNgamma.
- Matrix metalloproteinase (MMP) levels were assessed.
- Involvement of p38 and ERK1/2 MAPKs, TNFalpha, TNF receptors, and caspase 8 pathways were investigated using specific inhibitors and neutralizing antibodies.
- STAT1 phosphorylation was analyzed.
Main Results:
- IFNgamma alone did not affect monocyte MMP-1 or MMP-9.
- IFNgamma, in the presence of GM-CSF, induced MMP-1 and enhanced GM-CSF/TNFalpha-induced MMP-1 via TNFalpha stimulation, involving p38 and ERK1/2 MAPKs.
- IFNgamma inhibited TNFalpha-induced MMP-9 through a caspase 8-dependent pathway, which also affected STAT1 phosphorylation and p38 MAPK activity.
- Caspase 8 activation by IFNgamma did not lead to increased apoptosis.
Conclusions:
- IFNgamma differentially regulates monocyte MMPs in the presence of GM-CSF and/or TNFalpha.
- IFNgamma induces MMP-1 through TNFalpha stimulation and a novel caspase 8-dependent mechanism.
- IFNgamma inhibits MMP-9 via a caspase 8-dependent pathway that impacts STAT1 phosphorylation and p38 MAPK, independent of apoptosis.