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* Department of Pharmacology, Kyungpook National University School of Medicine, Daegu, Korea;
Department of Physiology, Institute of Health Science, Gyeongsang National University, Jinju, Korea;
Department of Genetic Engineering, School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Korea; and
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
Activated microglia are thought to undergo apoptosis as a self-regulatory mechanism. To better understand molecular mechanisms of the microglial apoptosis, apoptosis-resistant variants of microglial cells were selected and characterized. The expression of lipocalin 2 (lcn2) was significantly down-regulated in the microglial cells that were resistant to NO-induced apoptosis. lcn2 expression was increased by inflammatory stimuli in microglia. The stable expression of lcn2 as well as the addition of rLCN2 protein augmented the sensitivity of microglia to the NO-induced apoptosis, while knockdown of lcn2 expression using short hairpin RNA attenuated the cell death. Microglial cells with increased lcn2 expression were more sensitive to other cytotoxic agents as well. Thus, inflammatory activation of microglia may lead to up-regulation of lcn2 expression, which sensitizes microglia to the self-regulatory apoptosis. Additionally, the stable expression of lcn2 in BV-2 microglia cells induced a morphological change of the cells into the round shape with a loss of processes. Treatment of primary microglia cultures with the rLCN2 protein also induced the deramification of microglia. The deramification of microglia was closely related with the apoptosis-prone phenotype, because other deramification-inducing agents such as cAMP-elevating agent forskolin, ATP, and calcium ionophore also rendered microglia more sensitive to cell death. Taken together, our results suggest that activated microglia may secrete LCN2 protein, which act in an autocrine manner to sensitize microglia to the self-regulatory apoptosis and to endow microglia with an amoeboid form, a canonical morphology of activated microglia in vivo.
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1 This work was supported by the Neurobiology Research Program from the Korea Ministry of Science and Technology and by Grant R01-2006-000-10314-0 from the Basic Research Program of the Korea Science and Engineering Foundation. S.L., J.L., and S.K. were supported by the Brain Korea 21 Project in 2006. J.-Y.P. and K.S. were the recipients of the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2006-005-J04202; KRF-2006-311-E00045).
2 Address correspondence and reprint requests to Dr. Kyoungho Suk, Department of Pharmacology, School of Medicine, Kyungpook National University, 101 Dong-In, Joong-gu, Daegu, 700-422, Korea. E-mail address: ksuk{at}knu.ac.kr
3 Abbreviations used in this paper: LCN2, lipocalin 2; SNAP, S-nitroso-N-acetylpenicillamine; SNP, sodium nitroprusside; DFO, deferoxamine mesylate; shRNA, short hairpin RNA.
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