Urokinase-Type Plasminogen Activator Induces BV-2 Microglial Cell Migration Through Activation of Matrix Metalloproteinase-9 |
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Authors: | Sun Mi Shin Kyu Suk Cho Min Sik Choi Sung Hoon Lee Seol-Heui Han Young-Sun Kang Hee Jin Kim Jae Hoon Cheong Chan Young Shin Kwang Ho Ko |
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Affiliation: | (1) Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul, 151-742, Korea;(2) Institute for Biomedical Sciences and Technology, Konkuk University, Seoul, Korea;(3) Department of Pharmacology, School of Medicine, Konkuk University, Hwayang-Dong, Kwangjin-Gu, Seoul, 143-701, Korea;(4) Department of Psychiatry, School of Medicine, Konkuk University, Seoul, Korea;(5) Department of Biomedical Sciences and Technology, Konkuk University, Seoul, Korea;(6) Department of Pharmacology, School of Pharmacy, Samyook University, Seoul, Korea |
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Abstract: | In response to brain injury, microglia migrate and accumulate in the affected sites, which is an important step in the regulation of inflammation and neuronal degeneration/regeneration. In this study, we investigated the effect of urokinase-type plasminogen activator (uPA) on the BV-2 microglial cell migration. At resting state, BV-2 microglial cells secreted uPA and the release of uPA was increased by ATP, a chemoattractant released from injured neuron. The migration of BV-2 cell was significantly induced by uPA and inhibited by uPA inhibitors. In this condition, uPA increased the activity of matrix metalloproteinase (MMP-9) and the inhibition of MMP activity with pharmacological inhibitors against either uPA (amiloride) or MMP (phenanthrolene and SB-3CT) effectively prevented BV2 cell migration. Interestingly, the level of MMP-9 protein and mRNA in the cell were not changed by uPA. These results suggest that the increase of MMP-9 activity by uPA is regulated at the post-translational level, possibly via increased activation of the enzyme. Unlike the uPA inhibitor, plasmin inhibitor PAI-1 only partially inhibited uPA-induced cell migration and MMP-9 activation. The incubation of recombinant MMP-9 with uPA resulted in the activation of MMP-9. These results suggest that uPA plays a critical role in BV-2 microglial cell migration by activating pro-MMP-9, in part by its direct action on MMP-9 and also in part by the activation of plasminogen/plasmin cascade. |
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