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

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.

Acetylcholine Inhibits LPS-Induced MMP-9 Production and Cell Migration via the a7 nAChR-JAK2/STAT3 Pathway in RAW264.7 Cells

“…It has previously been shown that NF-κB and p38 MAPK play an important role in the regulation of MMP-9 and macrophage migration [11,14]. In the present study, we determined that NF-κB and p38 MAPK activation were markedly increased in RAW264.7 cells in response to LPS stimulation.…”

“…In contrast, signal transducer and activator of transcription 3 (STAT3), a potential anti-inflammatory mediator, can inhibit MMP-9 expression [13]. Other studies have demonstrated that activation of p38 mitogen-activated protein kinase (MAPK) and extracellular regulated protein kinases 1/2 (ERK1/2) up-regulated MMP-9 expression [12,14,15], while JNK (c-Jun N-Terminal kinase) phosphorylation reduced MMP-9 expression [15,16]. Thus, upstream regulators of MMP-9, such as STAT3 and NF-κB, may be utilized as therapeutic targets and can provide new insights into the treatment of many inflammatory diseases.…”

Gambling on putative biomarkers of osteoarthritis and osteochondrosis by equine synovial fluid proteomics

“…In particular, various deregulated proteins related to inflammatory status observed in OA have been reported also to play a direct/indirect effect on the enzymatic activity of matrix proteases and on extracellular matrix (ECM) turnover. For example, α2MG (up-regulated in OA - Table 2) modulates MMPs/ ADAMTs activity [56] and its macrophage production [57], plays a distinct role in ECM turnover [58] and is overexpressed in non-infectious equine arthritis [59], human OA, JA and RA [36,38,60]. Similarly, ITI-H1 (up-regulated in OA samples - Table 2) plays a prominent role in HA metabolism, affects the function of various matrix proteins and has been already associated with OA and RA [37,61].…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Atherosclerosis. Atherosclerosis is a pathological thickness of artery wall due to fatty acids and cholesterol deposition (Caceres et al, 2010). An early event in the onset of the disease is the altered permeability of the endothelial layer to LDL and fatty acids which then are loaded in the sub-endothelial space (Hansson, 2005).…”