title: Activated α(2) 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.
abstract: Macrophages under certain stimuli induce matrix metalloproteinase 9 (MMP-9) expression and protein secretion through the activation of MAPK-ERK and NF-κB signaling pathways. Previously, we demonstrated that activated α(2)-macroglulin (α(2)M*) through the interaction with its receptor low-density lipoprotein receptor-related protein 1 (LRP1) induces macrophage proliferation mediated by the activation of MAPK-ERK1/2. In the present work, we examined whether α(2)M*/LRP1interaction could induce the MMP-9 production in J774 and Raw264.7 macrophage-derived cell lines. It was shown that α(2)M* promoted MMP-9 expression and protein secretion by LRP1 in both macrophage-derived cell lines, which was mediated by the activation of MAPK-ERK1/2 and NF-κB. Both intracellular signaling pathways activated by α(2)M* were effectively blocked by calphostin-C, suggesting involvement of PKC. In addition, we demonstrate that α(2)M* produced extracellular calcium influx via LRP1. However, when the intracellular calcium mobilization was inhibited by BAPTA-AM, the α(2)M*-induced MAPK-ER1/2 activation was fully blocked in both macrophage cell lines. Finally, using specific pharmacological inhibitors for PKC, Mek1, and NF-κB, it was shown that the α(2)M*-induced MMP-9 protein secretion was inhibited, indicating that the MMP production promoted by the α(2)M*/LRP1 interaction required the activation of both signaling pathways. These findings may prove useful in the understanding of the macrophage LRP1 role in the vascular wall during atherogenic plaque progression.
authors.affiliation: Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Centro de Investigaciones en Bioquímica Clínica e Inmunología, Ciudad Universitaria 5000, Córdoba, Argentina.
authors.forename: Leandro C
authors.initials: LC
authors.lastname: Cáceres
authors.forename: Gustavo R
authors.initials: GR
authors.lastname: Bonacci
authors.forename: María C
authors.initials: MC
authors.lastname: Sánchez
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Chiabrando
mesh_terms: D000818:Animals; D050197:Atherosclerosis; D020013:Calcium Signaling; D002460:Cell Line; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D000511:alpha-Macroglobulins / Q000502:physiology*
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016328:NF-kappa B; D000511:alpha-Macroglobulins; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9