Won-Ha Lee

Kyungpook National University, Daikyū, Daegu, South Korea

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Publications (80)241.05 Total impact

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    ABSTRACT: Lipocalin-2 (LCN2) plays an important role in cellular processes as diverse as cell growth, migration/invasion, differentiation, and death/survival. Furthermore, recent studies indicate that LCN2 expression and secretion by glial cells are induced by inflammatory stimuli in the central nervous system (CNS). The present study was undertaken to examine the regulation of LCN2 expression in experimental autoimmune encephalomyelitis (EAE), and to determine the role of LCN2 in the disease process. LCN2 expression was found to be strongly increased in spinal cord and secondary lymphoid tissues after EAE induction. In spinal cords, astrocytes and microglia were the major cell types expressing LCN2 and its receptor 24p3R, respectively, whereas in spleens, LCN2 and 24p3R were highly expressed in neutrophils and dendritic cells, respectively. Furthermore, disease severity, inflammatory infiltration, demyelination, glial activation, the expression of inflammatory mediators, and the proliferation of MOG-specific T cells were significantly attenuated in Lcn2-deficient mice as compared with wild-type animals. MOG-specific T cells in culture exhibited an increased expression of Il17a, Ifng, Rorc, and Tbet after treatment with recombinant LCN2 protein. Moreover, LCN2-treated glial cells expressed higher levels of pro-inflammatory cytokines, chemokines, and MMP-9. Adoptive transfer and recombinant LCN2 protein injection experiments suggested that LCN2 expression in spinal cord and peripheral immune organs contributes to EAE development. Taken together, these results imply LCN2 is a critical mediator of autoimmune inflammation and disease development in EAE, and suggest that LCN2 be regarded a potential therapeutic target in multiple sclerosis.
    Journal of Biological Chemistry 05/2014; · 4.65 Impact Factor
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    ABSTRACT: Lipocalin-2 (LCN2) is an acute phase protein induced in response to injury, infection or other inflammatory stimuli. Based on the previously reported involvement of LCN2 in chemokine induction and in the recruitment of neutrophils at the sites of infection or tissue injury, we investigated the role of LCN2 in the pathogenesis of chronic/persistent inflammatory pain hypersensitivity. In the complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model, LCN2 expression was strongly induced in the ipsilateral hindpaws, peaking at 12hr after CFA injection and then gradually subsiding. In CFA-injected hindpaw tissues, LCN2 and its receptor 24p3R were mainly expressed in infiltrating neutrophils and macrophages. CFA-induced thermal hyperalgesia and mechanical allodynia were significantly diminished in Lcn2-deficient mice compared to wild-type animals. Furthermore, neutrophil infiltration, myeloperoxidase activity, expression of TNF-α, IL-1β and MIP-2 in CFA-injected hindpaws, and spinal glial activation were markedly reduced by Lcn2 deficiency. An intraplantar injection of recombinant LCN2 protein induced thermal and mechanical hypersensitivities in naïve mice, and this was accompanied by neutrophil and macrophage infiltration into the hindpaws and glial activation in the dorsal horn of the spinal cord. Taken together, our results show that inflammatory cell-derived LCN2 at the sites of inflammation plays important roles in central sensitization and the subsequent nociceptive behavior in the rodent model of chronic inflammatory pain.
    Experimental Neurology 01/2014; · 4.65 Impact Factor
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    ABSTRACT: Lipocalin-2 (LCN2) is an acute-phase protein induced by injury, infection, or other inflammatory stimuli. LCN2 binds small hydrophobic ligands and interacts with cell surface receptor to regulate diverse cellular processes. The role of LCN2 as a chemokine inducer in the central nervous system (CNS) has been previously reported. Based on the previous participation of LCN2 in neuroinflammation, we investigated the role of LCN2 in formalin-induced nociception and pathological pain. Formalin-induced nociceptive behaviors (licking/biting) and spinal microglial activation were significantly reduced in the second or late phase of the formalin test in Lcn2 knockout mice. Likewise, antibody-mediated neutralization of spinal LCN2 attenuated the mechanical hypersensitivity induced by peripheral nerve injury in mice. Taken together, our results suggest that LCN2 can be therapeutically targeted, presumably for both prevention and reversal of acute inflammatory pain as well as pathological pain.
    Immune Network 12/2013; 13(6):289-94.
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    ABSTRACT: Astrocytes provide structural and functional support for neurons, as well as display neurotoxic or neuroprotective phenotypes depending upon the presence of an immune or inflammatory microenvironment. This study was undertaken to characterize multiple phenotypes of activated astrocytes and to investigate the regulatory mechanisms involved. We report that activated astrocytes in culture exhibit two functional phenotypes with respect to pro- or anti-inflammatory gene expression, glial fibrillary acidic protein expression, and neurotoxic or neuroprotective activities. The two distinct functional phenotypes of astrocytes were also demonstrated in a mouse neuroinflammation model, which showed pro- or anti-inflammatory gene expression in astrocytes following challenge with classical or alternative activation stimuli; similar results were obtained in the absence of microglia. Subsequent studies involving recombinant lipocalin-2 (LCN2) protein treatment or Lcn2-deficient mice indicated that the pro- or anti-inflammatory functionally polarized phenotypes of astrocytes and their intracellular signaling pathway were critically regulated by LCN2 under in vitro and in vivo conditions. Astrocyte-derived LCN2 promoted classical proinflammatory activation of astrocytes but inhibited IL-4-STAT6 signaling, a canonical pathway involved in alternative anti-inflammatory activation. Our results suggest that the secreted protein LCN2 is an autocrine modulator of the functional polarization of astrocytes in the presence of immune or inflammatory stimuli and that LCN2 could be targeted therapeutically to dampen proinflammatory astrocytic activation and related pathologies in the CNS.
    The Journal of Immunology 10/2013; · 5.52 Impact Factor
  • Su-Geun Lim, Kyoungho Suk, Won-Ha Lee
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    ABSTRACT: LIGHT is a type II transmembrane protein belonging to the TNF superfamily which is involved in co-stimulation of T cells or apoptosis in tumors. In this study, the possibility of LIGHT-mediated reverse signaling was tested in the human monocytic leukemia cell line, THP-1. For stimulation of LIGHT, cells were stimulated with specific monoclonal antibody and changes in macrophage-related functions such as phagocytosis, adhesion, migration, cytokine secretion, and production of pro-inflammatory mediators were tested. Triggering of LIGHT induced production of pro-inflammatory mediators such as interleukin (IL)-8 and matrix metalloproteinase (MMP)-9 while suppressing the phagocytic activity. Utilization of signaling inhibitors and Western blot demonstrated that LIGHT activated ERK MAPK and PI3K and the major inflammatory transcription factor NF-κB. These data indicate that LIGHT-mediated signaling could modulate the macrophage activities and that successful regulation of its activity could be beneficial to the treatment of chronic inflammatory conditions where macrophages play an important role.
    Cellular Immunology 08/2013; 285(1-2):10-17. · 1.74 Impact Factor
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    ABSTRACT: Lipocalin 2 (LCN2), which is also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL), binds small, hydrophobic ligands and interacts with cell surface receptor 24p3R to regulate diverse cellular processes. In the present study, we examined the role of LCN2 in the pathogenesis of neuropathic pain using a mouse model of spared nerve injury (SNI). LCN2 mRNA levels were significantly increased in the dorsal horn of the spinal cord after SNI, and LCN2 protein was mainly localized in neurons of the dorsal and ventral horns. LCN2 receptor 24p3R was expressed in spinal neurons and microglia after SNI. LCN2-deficient mice exhibited significantly less mechanical pain hypersensitivity during the early phase after SNI, and an intrathecal injection of recombinant LCN2 protein elicited mechanical pain hypersensitivity in naive animals. LCN2 deficiency, however, did not affect acute nociceptive pain. LCN2-deficient mice showed significantly less microglial activation and proalgesic chemokine (CCL2 and CXCL1) production in the spinal cord after SNI than wild-type mice, and recombinant LCN2 protein induced the expressions of these chemokines in cultured neurons. Furthermore, the expression of LCN2 and its receptor was detected in neutrophils and macrophages in the sciatic nerve following SNI, suggesting the potential role of peripheral LCN2 in neuropathic pain. Taken together, our results indicate LCN2 plays a critical role in the development of pain hypersensitivity following peripheral nerve injury, and suggest that LCN2 mediates neuropathic pain by inducing chemokine expression and subsequent microglial activation.
    Journal of Biological Chemistry 07/2013; · 4.65 Impact Factor
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    ABSTRACT: Lysosome-associated membrane proteins (LAMPs), a family of highly glycosylated transmembrane proteins, are well known lysosomal markers. Recent investigations revealed the cell surface expression of LAMPs, especially after activation in various cell types. Although their role in lysosome function is under intense investigation, little is known about the function of this cell surface form of LAMPs. To investigate the role of cell surface LAMPs in macrophage activities, the human macrophage-like cell line THP-1 was stimulated with monoclonal antibodies specific to CD107a (LAMP-1) or CD107b (LAMP-2). Stimulation of CD107 enhanced LPS-induced IL-8 secretion and induced adhesion of THP-1 cells to culture plates coated with extracellular matrix proteins such as collagen, fibronectin, and laminin. Utilization of specific inhibitors of signaling adapters and Western blot analysis revealed that extracellular signal-regulated kinase (ERK) mediates the regulatory action of CD107. These results suggest that stimulation of THP-1 cells through CD107 affects macrophage-associated functions such as cytokine secretion and cellular adhesion through activation of ERK.
    Cellular Immunology 02/2013; 281(2):122-128. · 1.74 Impact Factor
  • Eun-Ju Kim, Kyoungho Suk, Won-Ha Lee
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    ABSTRACT: BACKGROUND: Src homology 2 domain-containing protein tyrosine phosphatase substrate (SHPS)-1 is known to have regulatory effects on myeloid cells. However, its role in macrophage activation is not clearly understood. METHODS AND RESULTS: In order to investigate the role of SHPS-1 in Toll-like receptor (TLR)-mediated activation, human monocytic cell lines were treated with anti-SHPS-1 monoclonal antibody. The triggering of SHPS-1 blocked the expression of IL-8 and TNF-α in cells treated with a TLR4 ligand that induces a signaling pathway involving myeloid differentiation factor 88 (MyD88) and Toll-interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF). Interestingly, SHPS-1 inhibited TLR9/MyD88-mediated, but not TLR3/TRIF-mediated, expression of IL-8. Accordingly, a synthetic peptide representing the immunoreceptor tyrosine-based inhibition motif (ITIM) of SHPS-1 suppressed only the MyD88 pathway. Utilization of specific inhibitors and Western blot analysis indicated that the inhibitory effects were mediated by Src homology 2 domain-containing phosphatases (SHPs) and phosphoinositide 3-kinase (PI3K). CONCLUSION: SHPS-1 negatively regulates the MyD88-dependent TLR signaling pathway through the inhibition of NF-κB activation.
    Agents and Actions 01/2013; · 1.59 Impact Factor
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    ABSTRACT: Activated macrophages are classified into two different forms: classically activated (M1) or alternatively activated (M2) macrophages. The presence of M1/M2 phenotypic polarization has also been suggested for microglia. Here, we report that the secreted protein lipocalin 2 (LCN2) amplifies M1 polarization of activated microglia. LCN2 protein (EC(50) 1 μg/ml), but not glutathione S-transferase used as a control, increased the M1-related gene expression in cultured mouse microglial cells after 8-24 h. LCN2 was secreted from M1-polarized, but not M2-polarized, microglia. LCN2 inhibited phosphorylation of STAT6 in IL-4-stimulated microglia, suggesting LCN2 suppression of the canonical M2 signaling. In the lipopolysaccharide (LPS)-induced mouse neuroinflammation model, the expression of LCN2 was notably increased in microglia. Primary microglial cultures derived from LCN2-deficient mice showed a suppressed M1 response and enhanced M2 response. Mice lacking LCN2 showed a markedly reduced M1-related gene expression in microglia after LPS injection, which was consistent with the results of histological analysis. Neuroinflammation-associated impairment in motor behavior and cognitive function was also attenuated in the LCN2-deficient mice, as determined by the rotarod performance test, fatigue test, open-field test, and object recognition task. These findings suggest that LCN2 is an M1-amplifier in brain microglial cells.-Jang, E., Lee, S., Kim, J.-H., Kim, J.-H., Seo, J.-W., Lee, W.-H., Mori, K., Nakao, K., Suk, K. Secreted protein lipocalin-2 promotes microglial M1 polarization.
    The FASEB Journal 12/2012; · 5.70 Impact Factor
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    ABSTRACT: The genomes of three South Korean Rinderpest virus vaccine strains (L72, LA77, and LA96) were analyzed in order to investigate their genetic variability. These three vaccine strains were all derived from the same virus strain origin (Fusan) through repeated passages in different culture systems. The full genome length of the three strains was 15,882 nucleotides, and the sequence similarity between the three South Korean RPV strains at the nucleotide level was 98.1 to 98.9%. The genetic distance between Nakamura III, L72, LA77, LA96, and LATC06 and the Kabete strain was greater than that between the Fusan and Kabete strains for the P, V, and C genes. The difference in pathogenicity among these strains might be due to the V gene, which has a positive (>1) selection ratio based on the analysis of synonymous (dS) and nonsynonymous (dN) substitution rates (dN/dS ratio [ω]).
    Journal of Virology 12/2012; 86(23):13115-6. · 5.08 Impact Factor
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    ABSTRACT: A multiplex reverse transcription polymerase chain reaction (mRT-PCR) assay was developed for the simultaneous detection of canine distemper virus (CDV), canine respiratory coronavirus (CRCoV), and canine influenza virus (CIV). These viral pathogens are all causative agents of canine infectious respiratory disease (CIRD). The sensitivity and specificity of the mRT-PCR were determined by comparing it to a rapid antigen test (RAT) or immuno-chromatography test kit and reverse transcription-polymerase chain reaction (RT-PCR) in the detection of CDV, CRCoV, and CIV antigens present in 100 clinical samples (nasal swabs and whole blood samples) from 50 dogs with respiratory disease symptoms. This study revealed that mRT-PCR had almost exactly the same performance or results were almost 100% in agreement with that of RT-PCR and RAT both in terms of the assay sensitivity and specificity which was more highly evident in detecting CIV, CDV, and CRCoV antigens present in canine nasal swab samples. Therefore, this assay could be a better alternative for the definitive and simultaneous ante-mortem detection of the three viral pathogens that cause CIRD by using nasal swabs.
    Journal of Veterinary Medical Science 09/2012; · 0.88 Impact Factor
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    ABSTRACT: To investigate the potential transmission of subtype H3 influenza virus to cats, a serological survey was carried out in South Korea. Serum samples (n = 1027) were obtained from 809 pet cats and 218 domesticated cats living in urban colonies (D-cats) from 2008 to 2010, and tested using an influenza anti-nucleoprotein (NP)-specific enzyme-linked immunosorbent assay (ELISA) and the haemagglutination inhibition (HI) test, which was recommended by the World Organization for Animal Health. Anti-influenza virus antibodies were detected in 3.12% and 2.43% of cat sera tested using the NP-specific ELISA and HI test, respectively. Anti-H3 antibodies were also identified when the HI assay was used for influenza virus serotyping. These data may indicate the sporadic transmission of subtype H3 influenza virus from other infected species to cats in South Korea.
    Journal of feline medicine and surgery. 07/2012; 14(10):746-50.
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    ABSTRACT: Decursin and related coumarin compounds in herbal extracts have a number of biological activities against inflammation, angiogenesis and cancer. We have analysed a derivative of decursin (CSL-32) for activity against inflammatory activation of cancer cells, such as migration, invasion and expression of pro-inflammatory mediators. The human fibrosarcoma cell line, HT1080, was treated with TNFα (tumour necrosis factor α) in the presence or absence of CSL-32. The cellular responses and modification of signalling adapters were analysed with respect to the production of pro-inflammatory mediators, as also migration, adhesion and invasion. Treatment of HT1080 cells with CSL-32 inhibited their proliferation, without affecting cell viability, and TNFα-induced expression of pro-inflammatory mediators, such as MMP-9 (matrix metalloproteinase-9) and IL-8 (interleukin-8). CSL-32 also suppressed phosphorylation and degradation of IκB (inhibitory κB), phosphorylation of p65 subunit of NF-κB (nuclear factor-κB) and nuclear translocation of NF-κB, which are required for the expression of pro-inflammatory mediators. In addition, CSL-32 inhibited invasion and migration of HT1080 cells, as also cellular adhesion to fibronectin, an ECM (extracellular matrix) protein. CSL-32 treatment resulted in a dose-dependent inhibition of PI3K (phosphoinositide 3-kinase) activity, required for the cellular migration. The analyses show that CSL-32 inhibits processes associated with inflammation, such as the production of pro-inflammatory mediators, as well as adhesion, migration and invasion in HT1080 cells.
    Cell Biology International 07/2012; 36(7):683-8. · 1.64 Impact Factor
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    ABSTRACT: Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of urokinase type plasminogen activators (uPA) and tissue type plasminogen activators (tPA), which mediate fibrinolysis. PAI-1 is also involved in the innate immunity by regulating cell migration and phagocytosis. However, little is known about the role of PAI-1 in the central nervous system. In this study, we identified PAI-1 in the culture medium of mouse mixed glial cells by liquid chromatography and tandem mass spectrometry. Secretion of PAI-1 from glial cultures was detected by ELISA and western blotting analysis. Cell migration was evaluated by in vitro scratch-wound healing assay or Boyden chamber assay and an in vivo stab wound injury model. Phagocytic activity was measured by uptake of zymosan particles. The levels of PAI-1 mRNA and protein expression were increased by lipopolysaccharide and interferon-γ stimulation in both microglia and astrocytes. PAI-1 promoted the migration of microglial cells in culture via the low-density lipoprotein receptor-related protein (LRP) 1/Janus kinase (JAK)/signal transducer and activator of transcription (STAT)1 axis. PAI-1 also increased microglial migration in vivo when injected into mouse brain. PAI-1-mediated microglial migration was independent of protease inhibition, because an R346A mutant of PAI-1 with impaired PA inhibitory activity also promoted microglial migration. Moreover, PAI-1 was able to modulate microglial phagocytic activity. PAI-1 inhibited microglial engulfment of zymosan particles in a vitronectin- and Toll-like receptor 2/6-dependent manner. Our results indicate that glia-derived PAI-1 may regulate microglial migration and phagocytosis in an autocrine or paracrine manner. This may have important implications in the regulation of brain microglial activities in health and disease.
    Journal of Neuroinflammation 06/2012; 9:149. · 4.35 Impact Factor
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    ABSTRACT: Increasing evidence supports that inflammation is closely associated with the development of cancer. In an effort to develop synthetic peptides that can suppress the inflammatory activation of cancer cells, decapeptides representing immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences of immune receptor expressed on myeloid cells-1 (IREM-1) were tested for their anti-inflammatory effects in cancer cell lines. One (named TAT-YADL) out of the five synthetic peptides tested exhibited inhibitory effects on the expression of inflammatory mediators as well as invasion and migration. The inhibitory activities of the synthetic peptides required activation of SH2-containing protein tyrosine phosphatase-1 (SHP-1) and phosphoinositide 3-kinase (PI3K).
    Cancer Investigation 06/2012; 30(5):364-71. · 2.24 Impact Factor
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    ABSTRACT: Jaceosidin is a naturally occurring flavone with pharmacological activity. Jaceosidin, as one of the major constituents of the medicinal herbs of the genus Artemisia, has been shown to exert anticancer, anti-oxidative, anti-inflammatory, and immunosuppressive effects. This study was undertaken to determine the effect of jaceosidin on microglia and neuroinflammation. Microglia are the innate immune cells in the central nervous system, and they play a central role in the initiation and maintenance of neuroinflammation. We report that jaceosidin inhibits inflammatory activation of microglia, reducing nitric oxide (NO) production and proinflammatory cytokine expression. IC(50) for NO inhibition was 27 ± 0.4 μM. The flavone also attenuated microglial neurotoxicity in the microglia/neuroblastoma co-culture. Systemic injection of jaceosidin ameliorated neuroinflammation in the mouse model of experimental allergic encephalomyelitis. These results indicate that plant flavone jaceosidin is a microglial inhibitor with anti-neuroinflammation activity. Copyright © 2012 John Wiley & Sons, Ltd.
    Phytotherapy Research 05/2012; · 2.07 Impact Factor
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    ABSTRACT: To evaluate a novel vaccine for porcine encephalomyocarditis virus (EMCV), which causes reproductive failure in pregnant sows, virus like particles (VLPs) were generated and immunized twice in 2week intervals before sow mating. Sows were divided into 4 groups (n=4, per group). Group 1 was immunized with the alum adjuvant alone, Group 2 with VLPs alone, Group 3 with VLPs mixed alum adjuvant, and Group 4 with a commercial killed vaccine. In Group 2, seroconversion was observed at very low levels, while in Group 3, neutralizing antibodies were maintained at a high level until 30days after farrowing. Similar levels neutralizing antibodies were observed in Group 4. The gestation period of the pregnant sows was on average 115days, and no injection site reaction or side effects were observed. The mean temperature of the sows after immunization increased temporarily to 38.7-39.1°C for 1day. The numbers and weights of surviving piglets were similar among the groups. These data describe a novel EMCV vaccine composed of VLPs mixed with an alum adjuvant that is safe to use during sow gestation and induces and maintains high levels of seroconversion. This vaccine could thus be a candidate for protecting against EMCV induced reproductive failure in pig farms.
    Research in Veterinary Science 03/2012; 93(3):1508-11. · 1.77 Impact Factor
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    ABSTRACT: A secreted protein, lipocalin-2 (LCN2), has been previously shown to regulate a variety of cellular phenotypes such as cell death, migration, and morphology. The role of LCN2, however, appears to be different depending on the cellular context. Here, we investigated how LCN2 influences neuronal phenotypes by using primary cortical neuronal cell cultures and neuroblastoma cell lines as a model. When exposed to LCN2 protein, neurons and neuroblastoma cells were sensitized to cell death evoked by nitric oxide, oxidative stress, and tumor necrosis factor-α (TNF-α). A forced expression of lcn2 in glia enhanced neuronal cell death in cocultures of glia and neurons, indicating that both exogenous protein addition and endogenous expression of lcn2 give rise to similar results. Iron and BCL2-interacting mediator of cell death (BIM) protein were involved in LCN2-induced cell death sensitization, based on the studies using iron donor, chelator, siderophore, and short hairpin RNA (shRNA)-mediated knockdown of bim expression. Furthermore, cell migration assay and immunofluorescence microscopic observation revealed that LCN2 accelerated neuronal motility and process extension, suggesting multiple roles for LCN2 in the regulation of neuronal cell death, migration, and morphology.
    Journal of Neuroscience Research 03/2012; 90(3):540-50. · 2.97 Impact Factor
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    ABSTRACT: Prostaglandin D synthase (PGDS) is responsible for the conversion of PGH(2) to PGD(2). Two distinct types of PGDS have been identified: hematopoietic-type PGDS (H-PGDS) and lipocalin-type PGDS (L-PGDS). L-PGDS acts as both a PGD(2)-synthesizing enzyme and as an extracellular transporter of various lipophilic small molecules. Although L-PGDS is one of the most abundant proteins in the cerebrospinal fluid, little is known about the function of L-PGDS in the central nervous system (CNS). To better understand the role of L-PGDS in the CNS, effects of L-PGDS on the migration and morphology of glial cells were investigated. The L-PGDS protein accelerated the migration of cultured glial cells. Expression of the L-pgds gene was detected in glial cells and neurons. L-PGDS protein also induced morphological changes in glia similar to the characteristic phenotypic changes in reactive gliosis. L-PGDS-induced cell migration was associated with augmented formation of actin filaments and focal adhesion, which was accompanied by activation of AKT, RhoA, and JNK pathways. L-PGDS protein injected into the mouse brain promoted migration and accumulation of astrocytes in vivo. Furthermore, the cell migration-promoting effect of L-PGDS on glial cells was independent of the PGD(2) products. The L-PGDS protein interacted with myristoylated alanine-rich protein kinase C substrate (MARCKS) to promote cell migration. These results demonstrate the critical role of L-PGDS as a secreted lipocalin in the regulation of glial cell migration and morphology. The results also indicate that L-PGDS may participate in reactive gliosis in an autocrine or paracrine manner, and may have pathological implications in neuroinflammatory diseases.
    Journal of Biological Chemistry 01/2012; 287(12):9414-28. · 4.65 Impact Factor
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    ABSTRACT: The secreted protein lipocalin-2 (LCN2) has been implicated in diverse cellular processes, including cell morphology and migration. Little is known, however, about the role of LCN2 in the CNS. Here, we show that LCN2 promotes cell migration through up-regulation of chemokines in brain. Studies using cultured glial cells, microvascular endothelial cells, and neuronal cells suggest that LCN2 may act as a chemokine inducer on the multiple cell types in the CNS. In particular, up-regulation of CXCL10 by JAK2/STAT3 and IKK/NF-κB pathways in astrocytes played a pivotal role in LCN2-induced cell migration. The cell migration-promoting activity of LCN2 in the CNS was verified in vivo using mouse models. The expression of LCN2 was notably increased in brain following LPS injection or focal injury. Mice lacking LCN2 showed the impaired migration of astrocytes to injury sites with a reduced CXCL10 expression in the neuroinflammation or injury models. Thus, the LCN2 proteins, secreted under inflammatory conditions, may amplify neuroinflammation by inducing CNS cells to secrete chemokines such as CXCL10, which recruit additional inflammatory cells.
    Journal of Biological Chemistry 12/2011; 286(51):43855-70. · 4.65 Impact Factor

Publication Stats

1k Citations
241.05 Total Impact Points

Institutions

  • 2004–2014
    • Kyungpook National University
      • • School of Food Science and Biotechnology
      • • Brain Science and Engineering Institute
      • • Department of Pharmacology
      Daikyū, Daegu, South Korea
  • 2005–2013
    • Kyungpook National University Hospital
      Sŏul, Seoul, South Korea
  • 2012
    • Konyang University
      • College of Medicine
      Ronsan, South Chungcheong, South Korea
    • Animal Plant And Fisheries Quarantine And Inspection Agency
      Anyō, Gyeonggi Province, South Korea
  • 2010–2011
    • National Veterinary Research Quarantine Service
      Sŏul, Seoul, South Korea
  • 2008
    • Konkuk University
      Sŏul, Seoul, South Korea
  • 2002–2005
    • Sungkyunkwan University
      • Samsung Medical Center
      Seoul, Seoul, South Korea