Activated α2 macroglobulin induces matrix metalloproteinase 9 expression by low density lipoprotein receptor-related protein 1 through MAPK-ERK1/2 and NF-κB activation in macrophage derived cell lines (original) (raw)
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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 +/2 or negatively-selected CD16 2 macrophages upregulated MMP-1, -3, -7, -10, -12, -14 and -25 and decreased TIMP-3 steady-state mRNA levels. Bacterial lipopolysaccharide, IL-1 and TNFa were more effective than interferonc 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 kB kinase-2. Effects of interferonc 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.
Cardiovascular …, 2001
Objective: Matrix metalloproteinases (MMPs) contribute to the destruction of the extracellular matrix at the shoulder regions of atherosclerotic plaques that leads to plaque destabilisation and triggers clinical cardiovascular disease. There is therefore considerable interest in establishing the mechanisms responsible for increased MMP production. MMPs-1,-3 and-9 are upregulated by inflammatory cytokines and growth factors that are produced by plaque resident macrophages and smooth muscle cells. Our present studies focused on NF-kB, which regulates numerous inflammatory genes, and is activated in plaque smooth muscle cells. Moreover, an NF-kB binding site is present in the promoter of the MMP-9 gene and an NF-kB-like element in the promoter of the MMP-1 gene. Methods: We used adenovirus mediated overexpression of its inhibitor, IkBa to investigate the role of NF-kB in regulation of MMP-1,-3 and-9 by isolated, cytokine stimulated rabbit aortic and human saphenous vein VSMC. Results: IL-1a potently activated NF-kB in VSMCs and acted synergistically with growth factors to upregulate expression of MMP-1,-3 and-9. Overexpression of IkBa, almost completely inhibited expression of MMP-1,-3 and-9 in response to IL-1a alone or in combination with bFGF and PDGF. Conclusion: NF-kB is required for cytokine upregulation of MMP-1,-3 and-9 in VSMCs, which suggests that NF-kB inhibition may promote plaque stabilisation.
Nutrition Research and Practice, 2008
Atherosclerosis is characterized by a chronic inflammatory disease, and chemokines play an important role in both initiation and progression of atherosclerosis development. Leukotactin-1 (Lkn-1/CCL15), a new member of the human CC chemokine family, is a potent chemoattractant for leukocytes. Our previous study has demonstrated that Lkn-1/CCL15 plays a role in the initiation of atherosclerosis, however, little is currently known whether Lkn-1/CCL15 is associated with the progression of atherosclerosis. Matrix metalloproteinases (MMPs) in human coronary atherosclerotic lesions play a crucial role in the progression of atherosclerosis by altering the vulnerability of plaque rupture. In the present study, we examined whether Lkn-1/CCL15 modulates MMP-9 release, which is a prevalent form expressed by activated macrophages and foam cells. Human THP-1 monocytic cells and/or human peripheral blood monocytes (PBMC) were treated with phorbol myristate acetate to induce their differentiation into macrophages. Foam cells were prepared by the treatment of THP-1 macrophages with human oxidized LDL. The macrophages and foam cells were treated with Lkn-1/CCL15, and the levels of MMP-9 release were measured by Gelatin Zymography. Lkn-1/CCL15 significantly enhanced the levels of MMP-9 protein secretion from THP-1 monocytic cells-derived macrophages, human PBMC-derived macrophages, as well as macrophage-derived foam cell in a dose dependent manner. Our data suggest that the action of Lkn-1/CCL15 on macrophages and foam cells to release MMP-9 may contribute to plaque destabilization in the progression of atherosclerosis.
2005
Macrophage migration inhibitory factor (MIF) has been shown to participate in both experimental and human atherogenesis. Expression of MMP-9 has been shown to play a role in the instability of atherosclerotic plaque. Thus, we hypothesize that MIF may participate in the destabilization of atherosclerotic plaques by stimulating MMP-9 expression. This hypothesis was investigated by examining the expression of MIF and MMP-9 in human atherosclerotic plaques using two-color immunostaining and by determining the potential role of MIF in the induction of MMP-9 expression in vascular smooth muscle cells (VSMC) and macrophages in vitro. Two-color immunohistochemistry demonstrated that MIF was strongly upregulated by macrophages and VSMCs. This was associated with marked increase in MMP-9 expression in vulnerable atheromatous plaques, but not in the fibrous lesions. Upregulation of MIF and MMP-9 in vulnerable atheromatous plaques was associated with the weakening of fibrous caps. The role of MIF in MMP-9 expression was demonstrated by the ability of MIF to directly induce MMP-9 mRNA and protein expression in macrophages and in VSMCs in a dose and time-dependent manner, which was blocked by a neutralizing MIF antibody. In conclusion, MIF and MMP-9 are markedly upregulated in vulnerable atheromatous plaques. The ability of MIF to induce MMP-9 expression in VSMCs and macrophages suggests that MIF may play a role in the destabilization of human atherosclerotic plaques.
Experimental Cell Research, 2008
MMP-12, a macrophage-specific matrix metalloproteinase with large substrate specificity, has been reported to be highly expressed in mice, rabbits and human atherosclerotic lesions. Increased MMP-12 from inflammatory macrophages is associated with several degenerative diseases such as atherosclerosis. In this manuscript, we show that IL-1β, a proinflammatory cytokine found in atherosclerotic plaques, increases both mRNA and protein levels of MMP-12 in human monocytederived macrophages (HMDM). Since peroxisome proliferator-activated receptors (PPARs), such as PPARα and PPARγ, are expressed in macrophages and because PPAR activation exerts an antiinflammatory effect on vascular cells, we have investigated the effect of PPARα and γ isoforms on MMP-12 regulation in HMDM. Our results show that MMP-12 expression (mRNA and protein) is down regulated in IL-1β-treated macrophages only in the presence of a specific PPARα agonist, GW647, in a dose-dependent manner. In contrast, this inhibitory effect was abolished in IL-1βstimulated peritoneal macrophages isolated from PPARα −/− mice and treated with the PPARα agonist, GW647. Moreover, reporter gene transfection experiments using different MMP-12 promoter constructs showed a reduction of the promoter activities by ∼ 50% in IL-1β-stimulated PPARα-pre-treated cells. However, MMP-12 promoter analysis did not reveal the presence of a PPRE response element. The IL-1β effect is known to be mediated through the AP-1 binding site. Mutation of the AP-1 site, located at − 81 in the MMP-12 promoter region relative to the transcription start site, followed by transfection analysis, gel shift and ChIP experiments revealed that the inhibitory effect was the consequence of the protein-protein interaction between GW 647-activated PPARα and c-Fos or c-Jun transcription factors, leading to inhibition of their binding to the AP-1 motif. These studies suggest that PPARα agonists may be used therapeutically, not only for lipid disorders, but also to prevent inflammation and atheromatous plaque rupture, where their ability to inhibit MMP-12 expression in HMDM may be beneficial.
C-Reactive Protein Induces Matrix Metalloproteinase-1 and -10 in Human Endothelial Cells
Journal of the American College of Cardiology, 2006
We examined the effect of C-reactive protein (CRP) on matrix metalloproteinase (MMP) and inhibitor expression in endothelial cells and in patients with clinical and subclinical atherosclerosis. BACKGROUND In addition to predicting atherosclerotic vascular disease, CRP may directly promote a proinflammatory/proatherosclerotic phenotype.
Journal of Biological Chemistry, 2002
Several matrix metalloproteinases (MMPs), including MMP-1,-3, and-9, mediate matrix destruction during chronic inflammatory diseases such as arthritis and atherosclerosis. MMP up-regulation by inflammatory cytokines involves interactions between several transcription factors, including activator protein-1 and nuclear factor B (NF-B). The upstream regulatory pathways are less well understood. We investigated the role of isoforms of protein kinase C (PKC) in basic fibroblast growth factor-and interleukin-1␣-mediated MMP production from cultured rabbit aortic smooth muscle cells. A synthetic PKC inhibitor, RO318220, inhibited MMP-1,-3, and-9 production by 89 ؎ 3, 75 ؎ 18, and 89 ؎ 9%, respectively. However, down-regulation of conventional and novel isoforms did not inhibit but rather increased MMP-9 production by 48 ؎ 16%, implicating an atypical PKC isoform. Consistent with this, PKC protein levels and activity were stimulated 3.3-and 13-fold, respectively, by basic fibroblast growth factor plus interleukin-1␣ and antisense oligonucleotides to PKC significantly decreased MMP-9 formation by 62 ؎ 18% compared with scrambled sequences. Moreover, adenovirus-mediated overexpression of a dominant-negative (DN) PKC reduced MMP-1,-3, and-9 production by 78 ؎ 9, 76 ؎ 8, and 76 ؎ 5%, respectively. DN-PKC inhibited NF-B DNA binding but did not affect ERK1/2 activation or AP-1 binding. Antisense PKC oligonucleotides and DN-PKC stimulated cell proliferation by 89 ؎ 14% (n ؍ 4) and 305 ؎ 74% (n ؍ 3), respectively (both p < 0.05). Our results show that PKC is essential for cytokine-induced up-regulation of MMP-1,-3, and-9, most likely by activating NF-B. Selective inhibition of PKC is therefore a possible strategy to inhibit MMP production in inflammatory diseases such as atherosclerosis.