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( Hyung Sik Kim ),( Min Young Park ),( Sung Kyun Lee ),( Joon Seong Park ),( Ha Young Lee ),( Yoe-sik Bae ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.8
Emergency granulopoiesis is a very important strategy to supply efficient neutrophil number in response to infection. However, molecular mechanism involved in this process remains unclear. Here, we found that administration of WKYMVm, an immune modulating peptide, to septic mice strongly increased neutrophil number through augmented emergency granulopoiesis. WKYMVm-induced emergency granulopoiesis was blocked not only by a formyl peptide receptor 2 (FPR2) antagonist (WRW4), but also by FPR2 deficiency. As progenitors of neutrophils, Lin<sup>-</sup>c-kit<sup>+</sup>Sca-1<sup>-</sup> cells expressed FPR2. WKYMVm-induced emergency granulopoiesis was also blocked by a phospholipase C inhibitor (U-73122). These results suggest that WKYMVm can stimulate emergency granulopoiesis via FPR2 and phospholipase C enzymatic activity. [BMB Reports 2018; 51(8): 418-423]
Kim, Jin‐,Sik,Yeo, Seungeun,Shin, Dong‐,Gu,Bae, Yoe‐,Sik,Lee, Jae‐,Jin,Chin, Byung‐,Rho,Lee, Chu‐,Hee,Baek, Suk‐,Hwan Blackwell Publishing Ltd 2010 FEBS JOURNAL Vol.277 No.13
<P>Macrophage activation contributes to the pathogenesis of atherosclerosis. In the vascular system, the major source of reactive oxygen species is the NADPH oxidase (Nox) family. Nox1 is induced by lipopolysaccharide (LPS) in macrophages, but the expression mechanism is not fully understood. We found that LPS causes β‐catenin accumulation by glycogen synthase kinase 3β (GSK3β) inactivation, and that β‐catenin accumulation increases Nox1 expression. LPS induced Nox1 mRNA expression and reactive oxygen species generation in Raw264.7 cells. Using bone marrow‐derived macrophages from toll‐like receptor 4 mutant mice, we also tested whether LPS‐induced Nox1 expression is toll‐like receptor 4 dependent. LPS caused GSK3β phosphorylation, induced β‐catenin accumulation and increased nuclear translocation. The GSK3β inhibitor LiCl potentiated LPS‐induced Nox1 expression in accordance with β‐catenin accumulation and nuclear translocation. Conversely, ectopic expression of a constitutively active GSK3β mutant severely attenuated Nox1 expression. These findings identify a novel regulatory pathway controlling Nox1 expression by LPS‐stimulated macrophages.</P>
Eun-Jung Lim,Yoe-Sik Bae,백석환,Dae-Weon Park,Jin-Gu Lee,이추희,Young-Chul Hwang,Jae-Weon Jeong,진병로 생화학분자생물학회 2010 Experimental and molecular medicine Vol.42 No.10
Synthetic oligodeoxynucleotides (ODN) with a CpGmotif are recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Stimulation of macrophages with TLR9 agonist prevented apoptosis induced by serum deprivation through increased expression of FLICE-like inhibitory protein (FLIP). CpG ODN-mediated anti-apoptosis depended on the TLR9-Akt-FoxO3a signaling pathway. Inhibition of TLR9 by small interfering (si) RNA or an inhibitor suppressed CpG ODN-mediated anti-apoptosis. Analysis of signaling pathways revealed that the anti-apoptotic effect of CpG ODN required phosphorylation of FoxO3a and its translocation from the nucleus to the cytosol. Overexpression of FoxO3a increased apoptosis induced by serum deprivation and CpG ODN blocked these effects through FLIP expression. In contrast,siRNA knock-down of FoxO3a decreased apoptosis by serum deprivation. In addition, Akt activation was involved in CpG ODN-induced phosphorylation of FoxO3a, expression of FLIP, and anti-apoptosis. Taken together, these results demonstrate the involvement of Akt-FoxO3a in TLR9-mediated anti-apoptosis and indicate that FoxO3a is a distinct regulator for FLIP expression.
Park, Yoo Jung,Kim, Hyung Sik,Lee, Ha Young,Hwang, Jae Sam,Bae, Yoe-Sik Elsevier 2017 Biochemical and biophysical research communication Vol. No.
<P><B>Abstract</B></P> <P>In this study, we identified scolopendrasin X, a novel antimicrobial peptide (AMP), from centipede <I>Scolopendra subspinipes mutilans</I>. Scolopendrasin X strongly stimulated mouse neutrophils, resulting in intracellular calcium increase, chemotactic migration through pertussis toxin-sensitive G-protein and phospholipase C pathway, and increased superoxide anion production in neutrophils. Target receptor for scolopendrasin X, formyl peptide receptor (FPR)2 mediated scolopendrasin X-induced neutrophil activation. Moreover, scolopendrasin X significantly blocked inflammatory cytokine production induced by lipopolysaccharide in mouse neutrophils. Taken together, our results suggest that the novel AMP scolopendrasin X can be used as a material to regulate neutrophil activity through FPR2.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A novel AMP scolopendrasin X stimulates calcium increase in neutrophils. </LI> <LI> Scolopendrasin X stimulates neutrophil chemotaxis via FPR2. </LI> <LI> Scolopendrasin X stimulates superoxide anion production in neutrophils. </LI> <LI> Scolopendrasin X blocks LPS-induced inflammatory cytokine production. </LI> <LI> A novel agonist for FPR2 regulates infectious/inflammatory responses. </LI> </UL> </P>
Shin, Myeong Heon,Lee, Young-Ah,Bae, Yoe-Sik,Kita, Hirohito,Kim, Youngdong,Ryu, Sung Ho S. Karger AG 2005 International archives of allergy and immunology Vol.137 No.suppl1
<P><I>Background:</I> Eosinophils play a key role in allergic inflammation and parasitic infections. The synthetic peptide, Trp-Lys-Tyr-Met-Val-<I>D</I>-Met (WKYMVm), has been previously shown to activate eosinophils and thus to enhance respiratory burst through the formyl peptide receptors. <I>Objective:</I> This study was undertaken to determine the intracellular signaling pathway involved in WKYMVm-stimulated superoxide production by human eosinophils. <I>Methods:</I> Purified eosinophils from peripheral blood were stimulated with various concentrations (10<SUP>-3</SUP> to 10 μ<I>M</I>) of WKYMVm and the involvement of PI3-kinase and MAP kinases in WKYMVm-triggered superoxide production was investigated using pharmacological inhibitors. <I>Results:</I> WKYMVm-induced superoxide production by eosinophils was strongly inhibited by pretreatment with the PI3-kinase inhibitor LY294002. In addition, pretreatment with the ERK1/2 kinase inhibitor PD98059 resulted in marked inhibition of superoxide production induced by WKYMVm. Indeed, WKYMVm strongly induced phosphorylation of ERK1/2. The ERK1/2 activation by the peptide was transient and peaked after 2 min of stimulation. Furthermore, ERK1/2 activation by WKYMVm was completely inhibited by pretreatment with the PI3-kinase inhibitor LY294002, but not by the PKC inhibitor Ro-31-8220. <I>Conclusion:</I> These results suggest that WKYMVm stimulates human eosinophils to induce superoxide production via a PI3-kinase-mediated ERK1/2 pathway.</P><P>Copyright © 2005 S. Karger AG, Basel</P>
Sphingosylphosphorylcholine stimulates human monocyte-derived dendritic cell chemotaxis
LEE, Ha-young,SHIN, Eun-ha,BAE, Yoe-sik Springer Science and Business Media LLC 2006 Acta pharmacologica Sinica. Vol.27 No.10
<P>Aim: To investigate the effects of sphingosylphosphorylcholine (SPC) on human monocyte-derived dendritic cell (DC) chemotaxis. Methods: Human DC were generated from peripheral blood monocytes by culturing them with granulocyte macrophage-colony stimulating factor and interleukin-4. The effect of SPC on the DC chemotactic migration was measured by chemotaxis assay. Intracellular signaling event involved in the SPC-induced DC chemotaxis was investigated with several inhibitors for specific kinase. The expression of the SPC receptors was examined by reverse transcription polymerase chain reaction. Results: We found that SPC induced chemotactic migration in immature DC (iDC) and mature DC (mDC). In terms of SPC-induced signaling events, mitogen activated protein kinase activation and Akt activation in iDC and mDC were stimulated. SPC-induced chemotaxis was mediated by extracellular signal-regulated protein kinase and phosphoino-sitide-3-kinase, but not by calcium in both iDC and mDC. Although mDC express ovarian cancer G protein-coupled receptor 1, but not G protein-coupled receptor 4, iDC do not express any of these receptors. To examine the involvement of sphingosine-1-phosphate (S1P) receptors, we checked the effect of an S1P receptor antagonist (VPC23019) on SPC-induced DC chemotaxis. VPC23019 did not affect SPC-induced DC chemotaxis. Conclusion: The results suggest that SPC may play a role in regulating DC trafficking during phagocytosis and the T cell-stimulating phase, and the unique SPC receptor, which is different from S1P receptors, is involved in SPC-induced chemotaxis.</P>
Kim, Youndong,Lee, Byoung Dae,Kim, Oekyung,Bae, Yoe-Sik,Lee, Taehoon,Suh, Pann-Ghill,Ryu, Sung Ho Williams Wilkins 2006 JOURNAL OF IMMUNOLOGY Vol.176 No.5
<P>Although the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in the regulation of several immune responses, its target receptors and signaling mechanisms have yet to be fully elucidated in immune cells. In this study, we found that PACAP27, but not PACAP38, specifically stimulated intracellular calcium mobilization and ERK phosphorylation in human neutrophils. Moreover, formyl peptide receptor-like 1 (FPRL1) was identified as a PACAP27 receptor, and PACAP27 was found to selectively stimulate intracellular calcium increase in FPRL1-transfected rat basophil leukocytes-2H3 cell lines. In addition, PACAP27-induced calcium increase and ERK phosphorylation were specifically inhibited by an FPRL1 antagonist, Trp-Arg-Trp-Trp-Trp-Trp (WRW4), thus supporting the notion that PACAP27 acts on FPRL1. In terms of the functional role of PACAP27, we found that the peptide stimulated CD11b surface up-regulation and neutrophil chemotactic migration, and that these responses were completely inhibited by WRW4. The interaction between PACAP27 and FPRL1 was analyzed further using truncated PACAPs and chimeric PACAPs using vasoactive intestinal peptide, and the C-terminal region of PACAP27 was found to perform a vital function in the activation of FPRL1. Taken together, our study suggests that PACAP27 activates phagocytes via FPRL1 activation, and that this results in proinflammatory behavior, involving chemotaxis and the up-regulation of CD11b.</P>
Functional roles of sphingolipids in immunity and their implication in disease
Lee Min Gyu,Lee Suh Yeon,Bae Yoe-Sik 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Sphingolipids, which are components of cellular membranes and organ tissues, can be synthesized or degraded to modulate cellular responses according to environmental cues, and the balance among the different sphingolipids is important for directing immune responses, regardless of whether they originate, as intra- or extracellular immune events. Recent progress in multiomics-based analyses and methodological approaches has revealed that human health and diseases are closely related to the homeostasis of sphingolipid metabolism, and disease-specific alterations in sphingolipids and related enzymes can be prognostic markers of human disease progression. Accumulating human clinical data from genome-wide association studies and preclinical data from disease models provide support for the notion that sphingolipids are the missing pieces that supplement our understanding of immune responses and diseases in which the functions of the involved proteins and nucleotides have been established. In this review, we analyze sphingolipid-related enzymes and reported human diseases to understand the important roles of sphingolipid metabolism. We discuss the defects and alterations in sphingolipid metabolism in human disease, along with functional roles in immune cells. We also introduce several methodological approaches and provide summaries of research on sphingolipid modulators in this review that should be helpful in studying the roles of sphingolipids in preclinical studies for the investigation of experimental and molecular medicines.