Inhibition of MMP‐3 or ‐9 suppresses lipopolysaccharide‐induced expression of proinflammatory cytokines and iNOS in microglia

Abstract

Recently, matrix metalloproteinases (MMPs) are emerging as important molecules in neuroinflammation as well as neuronal cell death. However, the role of MMPs in activated microglia remains unclear. In the present study, we found that expressions of MMP‐1, ‐3, ‐8 and ‐9 were significantly induced by single or combined treatment of immunostimulants lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) in primary cultured microglia and BV2 microglial cells. Inhibition of MMP‐3 or ‐9 significantly suppressed the expression of iNOS and pro‐inflammatory cytokines and the activities of NF‐κB, AP‐1, and MAPK in LPS‐stimulated microglia. The results suggest that MMP‐3 and ‐9 both mediate LPS‐induced inflammatory reactions. Inhibition of reactive oxygen species (ROS) by N‐acetyl‐cysteine or diphenylene iodonium significantly suppressed the expression of MMP‐3, MMP‐9, NO and TNF‐α in LPS‐stimulated microglia, suggesting that ROS is an early signaling inducer in LPS‐stimulated microglial cells. MMP inhibitors also suppressed ROS production, suggesting a cross‐talk between ROS and MMPs. Collectively, the present study demonstrates that MMP‐3 and MMP‐9 play a role as inflammatory mediators in activated microglia. Pharmacological intervention of MMPs especially MMP‐3 and ‐9 would be a therapeutic strategy for the treatment of inflammatory diseases in the CNS caused by over‐activation of microglial cells.

Betulinic Acid Inhibits LPS-Induced MMP-9 Expression by Suppressing NF-kB Activation in BV2 Microglial Cells

“…Recently, it has been reported that increased expression and activity of MMP-9 are involved in microglial activation and that the inhibition of MMP-9 suppresses LPSinduced expression of pro-infl ammatory cytokines in microglia (Woo et al, 2008). In the present study, betulinic acid significantly attenuated the LPS-induced MMP-9 expression.…”

α-Synuclein Activates Microglia by Inducing the Expressions of Matrix Metalloproteinases and the Subsequent Activation of Protease-Activated Receptor-1

“…Recently, we reported that the inhibition of MMP-3 or MMP-9 also suppresses microglial activation in LPS-stimulated microglial cells (42). The results suggest that MMPs may play a role as common molecules that mediate inflammatory reactions and that PAR-1 is closely associated with the plausible mechanisms for MMP-mediated microglial activation.…”

The Significance of Matrix Metalloproteinases in the Immunopathogenesis and Treatment of Multiple Sclerosis = أهمية الأنزيمات المعدنية المحللة للبروتين في تطور مرض التصلب العصبي المتعدد و علاجه

“…52 Moreover, the release of MMP-3 into the ECM activates microglial or brain cells in the white matter. 53 Some evidence strongly suggests that the distinctive signal of neuronal apoptosis is the release of the active form of MMP-3 that activates the microglia and subsequently exacerbates neuronal degeneration. 54 It has been shown consistently that the inhibition of MMP-3 leads to the suppression of inducible nitric oxide synthase, (iNOS), proinflammatory cytokines and the inflammatory transcription factors nuclear factor kappa B (NF-κB), activator protein 1 (AP1) and mitogen-activated protein kinases (MAPKs) in the microglia.…”