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Yoe-sik Bae - One of the best experts on this subject based on the ideXlab platform.
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A novel antimicrobial Peptide acting via Formyl Peptide Receptor 2 shows therapeutic effects against rheumatoid arthritis
Nature Publishing Group, 2018Co-Authors: Yoo Jung Park, Jae-sam Hwang, Ha Young Lee, Byunghyun Park, Mingyu Lee, Yu Sun Jeong, Dong Hyun Sohn, Jason Jungsik Song, Joon Ha Lee, Yoe-sik BaeAbstract:Abstract In oriental medicine, centipede Scolopendra subspinipes mutilans has long been used as a remedy for rheumatoid arthritis (RA), a well-known chronic autoimmune disorder. However, the molecular identities of its bioactive components have not yet been extensively investigated. We sought to identify bioactive molecules that control RA with a centipede. A novel antimicrobial Peptide (AMP) (scolopendrasin IX) was identified from Scolopendra subspinipes mutilans. Scolopendrasin IX markedly activated mouse neutrophils, by enhancing cytosolic calcium increase, chemotactic cellular migration, and generation of superoxide anion in neutrophils. As a target Receptor for scolopendrasin IX, Formyl Peptide Receptor (FPR)2 mediates neutrophil activation induced by the AMP. Furthermore, scolopendrasin IX administration strongly blocked the clinical phenotype of RA in an autoantibody-injected model. Mechanistically, the novel AMP inhibited inflammatory cytokine synthesis from the joints and neutrophil recruitment into the joint area. Collectively, we suggest that scolopendrasin IX is a novel potential therapeutic agent for the control of RA via FPR2
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fam19a5 a brain specific chemokine inhibits rankl induced osteoclast formation through Formyl Peptide Receptor 2
Scientific Reports, 2017Co-Authors: Min Young Park, Ha Young Lee, Byunghyun Park, Mingyu Lee, Hyung Sik Kim, Eun Bee Cho, Jae Young Seong, Yoe-sik BaeAbstract:Osteoclasts can be differentiated from bone marrow-derived macrophages (BMDM). They play a key role in bone resorption. Identifying novel molecules that can regulate osteoclastogenesis has been an important issue. In this study, we found that FAM19A5, a neurokine or brain-specific chemokine, strongly stimulated mouse BMDM, resulting in chemotactic migration and inhibition of RANKL-induced osteoclastogenesis. Expression levels of osteoclast-related genes such as RANK, TRAF6, OSCAR, TRAP, Blimp1, c-fos, and NFATc1 were markedly decreased by FAM19A5. However, negative regulators of osteoclastogenesis such as MafB and IRF-8 were upregulated by FAM19A5. FAM19A5 also downregulated expression levels of RANKL-induced fusogenic genes such as OC-STAMP, DC-STAMP, and Atp6v0d2. FAM19A5-induced inhibitory effect on osteoclastogenesis was significantly reversed by a Formyl Peptide Receptor (FPR) 2 antagonist WRW4 or by FPR2-deficiency, suggesting a crucial role of FPR2 in the regulation of osteoclastogenesis. Collectively, our results suggest that FAM19A5 and its target Receptor FPR2 can act as novel endogenous ligand/Receptor to negatively regulate osteoclastogenesis. They might be regarded as potential targets to control osteoclast formation and bone disorders.
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Proteomic Analysis of the Palmitate-induced Myotube Secretome Reveals Involvement of the Annexin A1-Formyl Peptide Receptor 2 (FPR2) Pathway in Insulin Resistance
Molecular & cellular proteomics : MCP, 2015Co-Authors: Jong Hyuk Yoon, Dayea Kim, Jin-hyeok Jang, Jaewang Ghim, Soyeon Park, Parkyong Song, Yonghoon Kwon, Jaeyoon Kim, Daehee Hwang, Yoe-sik BaeAbstract:Elevated levels of the free fatty acid palmitate are found in the plasma of obese patients and induce insulin resistance. Skeletal muscle secretes myokines as extracellular signaling mediators in response to pathophysiological conditions. Here, we identified and characterized the skeletal muscle secretome in response to palmitate-induced insulin resistance. Using a quantitative proteomic approach, we identified 36 secretory proteins modulated by palmitate-induced insulin resistance. Bioinformatics analysis revealed that palmitate-induced insulin resistance induced cellular stress and modulated secretory events. We found that the decrease in the level of annexin A1, a secretory protein, depended on palmitate, and that annexin A1 and its Receptor, Formyl Peptide Receptor 2 agonist, played a protective role in the palmitate-induced insulin resistance of L6 myotubes through PKC-θ modulation. In mice fed with a high-fat diet, treatment with the Formyl Peptide Receptor 2 agonist improved systemic insulin sensitivity. Thus, we identified myokine candidates modulated by palmitate-induced insulin resistance and found that the annexin A1- Formyl Peptide Receptor 2 pathway mediated the insulin resistance of skeletal muscle, as well as systemic insulin sensitivity.
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Activation of human monocytes by a Formyl Peptide Receptor 2-derived pepducin.
FEBS letters, 2010Co-Authors: Ha Young Lee, Joon-seong Park, Sang Doo Kim, Jae Woong Shim, Hak Jung Kim, Jae Young Kwon, Jong-min Kim, Suk-hwan Baek, Yoe-sik BaeAbstract:We synthesized and investigated the effect of Formyl Peptide Receptor 2 (FPR2)-derived pepducins in human monocytes. The FPR2-based cell-penetrating lipoPeptide, "pepducin" (F2pal-16), stimulated intracellular calcium increase in human monocytes via pertussis toxin (PTX)-sensitive G-protein and phospholipase C (PLC) activity. From a functional aspect, we showed that F2pal-16 stimulated monocyte chemotaxis. F2pal-16 also stimulated the generation of superoxide anion in human monocytes. Moreover, F2pal-16 dramatically increased the production of several kinds of pro-inflammatory cytokines (CXCL8, CCL2, IL-1β and TNF-α) in human monocytes via NF-κB activation. Since FPR2 plays an important role in immune responses, F2pal-16 can serve as a useful reagent for the study of FPR2-mediated immune modulation.
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the synthetic Peptide trp lys tyr met val d met inhibits human monocyte derived dendritic cell maturation via Formyl Peptide Receptor and Formyl Peptide Receptor like 2
Journal of Immunology, 2005Co-Authors: Hyun Kyu Kang, Ha Young Lee, Mikyoung Kim, Kyoung Sun Park, Yeong Min Park, Jongyoung Kwak, Yoe-sik BaeAbstract:Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm) has been reported to stimulate monocytes, neutrophils, and dendritic cells (DCs). However, although WKYMVm has been reported to function as a DC chemoattractant, its role on DC maturation has not been examined. In this study, we investigated the effects of WKYMVm on human DC maturation. The costimulation of DCs with WKYMVm and LPS dramatically inhibited LPS-induced IL-12 production, CD86 and HLA-DR surface expression, and DC-mediated T cell proliferation. However, DC phagocytic activity was increased by WKYMVm stimulation. These findings demonstrate that WKYMVm inhibits DC maturation by LPS. In terms of the mechanism underlying DC maturation inhibition by WKYMVm, we found that LPS-induced DC maturation was negatively regulated by WKYMVm-stimulated ERK activity. Moreover, the costimulation of DCs with WKYMVm and LPS dramatically inhibited the LPS-induced accumulations of IL-12 mRNA, thus suggesting that WKYMVm inhibits LPS-induced IL-12 production at the transcriptional level. We also found that DCs express two WKYMVm Receptors, Formyl Peptide Receptor (FPR) and FPR-like 2 (FPRL2). In addition, Formyl-Met-Leu-Phe (a FPR ligand), Trp-Lys-Tyr-Met-Val-Met, Hp(2-20) Peptide, and F2L (three FPRL2 ligands) inhibited LPS-induced IL-12 production in DCs. Taken together, our findings indicate that the activations of FPR and FPRL2 inhibit LPS-induced DC maturation, and suggest that these two Receptors should be regarded as important potential therapeutic targets for the modulation of DC maturation.
Christine Wenneras - One of the best experts on this subject based on the ideXlab platform.
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Cyclosporin H, Boc-MLF and Boc-FLFLF are Antagonists that Preferentially Inhibit Activity Triggered Through the Formyl Peptide Receptor
Inflammation, 2007Co-Authors: Annalena Stenfeldt, Christine Wenneras, Huamei Fu, Jennie Karlsson, Johan Bylund, Claes DahlgrenAbstract:In order to properly interpret Receptor inhibition experiments, the precise Receptor specificities of the employed antagonists are of crucial importance. Lately, a great number of agonists for various Formyl Peptide Receptors have been identified using a selection of antagonists. However, some confusion exists as to the precise Receptor specificities of many of these antagonists. We have investigated the effects of Formyl Peptide Receptor family antagonists on the neutrophil response induced by agonists for the Formyl Peptide Receptor (FPR) and the Formyl Peptide Receptor like 1 (FPRL1). To determine FPR- and FPRL1-specific interactions, these antagonists should not be used at used at concentrations above 10 μM. Signaling through FPR was inhibited by low concentrations of the antagonists cyclosporin H, Boc-MLF (also termed Boc-1), and Boc-FLFLFL (also termed Boc-2), while higher concentrations also partly inhibited the signaling through FPRL1. The antagonist WRWWWW (WRW_4) specifically inhibited the signaling through FPRL1 at low concentrations but at high concentrations also partly the signaling through FPR. Based on the difference in potency of cyclosporin H and the two Boc-Peptides, we suggest using cyclosporin H as a specific inhibitor for FPR. To specifically inhibit the FPRL1 response the antagonist WRW_4 should be used.
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the non steroidal anti inflammatory drug piroxicam blocks ligand binding to the Formyl Peptide Receptor but not the Formyl Peptide Receptor like 1
Biochemical Pharmacology, 2007Co-Authors: Annalena Stenfeldt, Christine Wenneras, Huamei Fu, Jennie Karlsson, Johan Bylund, Claes DahlgrenAbstract:The anti-inflammatory drug piroxicam has been reported to affect the production of reactive oxygen species in phagocytes. This anti-inflammatory effect is thought to be mediated through inhibition of cyclooxygenase (COX), an enzyme important for prostaglandin synthesis. We have compared the effects of piroxicam on superoxide production mediated by two closely related G-protein coupled Receptors expressed on neutrophils, the Formyl Peptide Receptor (FPR) and the Formyl Peptide Receptor like 1 (FPRL1). Neutrophils were stimulated with agonists that bind specifically to FPR (the Peptide ligand N-Formyl-Met-Leu-Phe, fMLF) or FPRL1 (the Peptide ligand Trp-Lys-Tyr-Met-Val-L-Met-NH2, WKYMVM) or both of these Receptors (the Peptide ligand Trp-Lys-Tyr-Met-Val-D-Met-NH2, WKYMVm). Piroxicam reduced the neutrophil superoxide production induced by the FPR agonist but had no significant effect on the FPRL1 induced response. Neutrophil intracellular calcium changes induced by the agonist WKYMVm (that triggers both FPR and FPRL1) were only inhibited by piroxicam when the drug was combined with the FPRL1 specific antagonist, Trp-Arg-Trp-Trp-Trp-Trp (WRW4), and this was true also for the inhibition of superoxide anion release. Receptor-binding analysis showed that the fluorescently labelled FPR specific ligand N-Formyl-Nle-Leu-Phe-Nle-Tyr-Lys (fNLFNYK), was competed for in a dose-dependent manner, by the FPR ligand fMLF and as well as by piroxicam. We show that piroxicam inhibits the neutrophil responses triggered through FPR, but not through FPRL1 and this inhibition is due to a reduced binding of the activating ligand to its cell surface Receptor.
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House dust mite allergen activates human eosinophils via Formyl Peptide Receptor and Formyl Peptide Receptor-like 1.
European journal of immunology, 2007Co-Authors: Lena Svensson, Jennie Karlsson, Marie-josèphe Rabiet, Claes Dahlgren, Elin Redvall, Camilla Björn, Ann-marie H. Bergin, Christine WennerasAbstract:The objective was to evaluate which Receptors house dust mite (HDM) and birch pollen extracts engage to activate human eosinophils. Chemotaxis and degranulation were studied in eosinophils pretreated with pertussis toxin and other antagonists of G protein-coupled Receptors, e.g. the Formyl Peptide Receptor (FPR), CC chemokine Receptor 3 (CCR3) and leukotriene Receptor B4 (LTB(4)R). Inhibition of the FPR as well as desensitization of the Receptor rendered eosinophils anergic to activation by the allergens. Blockade of CCR3 or LTB(4)R did not affect eosinophilic reactivity. It was determined by PCR that human eosinophils express the FPR family members FPR and FPR-like 1 (FPRL1). HDM, unlike birch pollen, evoked calcium fluxes in HL-60 cells transfected with FPR or FPRL1. Although both allergens gave rise to calcium transients in neutrophils, which also express FPR and FPRL1, only the HDM response was decreased by the FPR antagonist. Moreover, neutrophils migrated toward HDM but not to birch pollen. Eosinophils pretreated with inhibitors of MAPK p38, ERK1/2 or protein kinase C exhibited diminished responsiveness to the aeroallergens. This study indicates that FPR and FPRL1 mediate the activation of eosinophils by HDM, whereas birch pollen employs other pathways shared with FPR to activate human eosinophils.
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The chemoattractant Trp-Lys-Tyr-Met-Val-D-Met activates eosinophils through the Formyl Peptide Receptor and one of its homologues, Formyl Peptide Receptor-like 1
Journal of leukocyte biology, 2002Co-Authors: Lena Svensson, Claes Dahlgren, Christine WennerasAbstract:Whereas prokaryotes use L- and D-isomers of amino acids in their protein synthesis, eukaryotic proteins as a rule incorporate only L-isomers. Hence, D-isomers may constitute danger signals to the innate immune system. A D-methionine-containing Peptide, Trp-Lys-Tyr-Met-Val-D-Met-NH(2) (WKYMVm), has been shown to be a stronger activator of neutrophils than f-Met-Leu-Phe. The aim of this study was to compare the responsiveness of eosinophils to WKYMVm with that of neutrophils. The Peptide was found to induce chemotaxis and respiratory burst in eosinophils. However, it did not mobilize granule constituents, as evidenced by a lack of eosinophil cationic protein, eosinophil peroxidase, and interleukin-5 in the supernatants of stimulated eosinophils. In contrast, WKYMVm caused the release of complement Receptor 3 from secretory vesicles in neutrophils. Different members of the Formyl Peptide Receptor family were preferentially engaged by the Peptide in the two classes of granulocytes: the Formyl Peptide Receptor itself in eosinophils and Formyl Peptide Receptor-like 1 in neutrophils.
Claes Dahlgren - One of the best experts on this subject based on the ideXlab platform.
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combining elements from two antagonists of Formyl Peptide Receptor 2 generates more potent peptidomimetic antagonists
Journal of Medicinal Chemistry, 2017Co-Authors: Sarah Line Skovbakke, Claes Dahlgren, Huamei Forsman, Andre Holdfeldt, Christina Nielsen, Anna Mette Hansen, Iris Perezgassol, Henrik FranzykAbstract:Structural optimization of a peptidomimetic antagonist of Formyl Peptide Receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived Peptide (i.e., PBP10, RhB-QRLFQVKGRR-OH) and the palmitoylated α-Peptide/β-peptoid hybrid Pam-(Lys-βNspe)6-NH2. This generated an array of hybrid compounds from which a new subclass of Receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective antagonists (i.e., RhB-(Lys-βNphe)n-NH2; n = 4–6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease.
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Antibacterial Activity of Pepducins, Allosterical Modulators of Formyl Peptide Receptor Signaling
Antimicrobial agents and chemotherapy, 2014Co-Authors: Malene Winther, Francois Boulay, Claes Dahlgren, Johan Bylund, Michael Gabl, Tudor I. Oprea, Bodil Jönsson, Huamei ForsmanAbstract:Pepducins containing a fatty acid linked to an amino acid sequence derived from cytosolic parts of a G-protein-coupled Receptor (GPCR) constitute a new group of lipoPeptide tools in GPCR studies. Pepducins corresponding to the third intracellular loop of Formyl Peptide Receptor 2 (FPR2) activate human neutrophils, and we show here that, in addition, these allosteric modulators of Receptor activity also kill bacteria. The functional dualism of FPR2 pepducins could potentially be explored as a novel class of antibacterial drugs with immunomodulatory properties.
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Tumour necrosis factor (TNF)-alpha primes murine neutrophils when triggered via Formyl Peptide Receptor-related sequence 2, the murine orthologue of human Formyl Peptide Receptor-like 1, through a process involving the type I TNF Receptor and subcell
Immunology, 2008Co-Authors: Karin Onnheim, Francois Boulay, Claes Dahlgren, Johan Bylund, Huamei ForsmanAbstract:Neutrophil granulocytes play an important role in innate host defence against microbial invasions and they are also the key effector cells in mediating host tissue damage. These functions often rely on the production of reactive oxygen species (ROS) from the membrane-bound NADPH-oxidase system. The magnitude of ROS production varies depending on the state of the cells, i.e. resting or primed. Many priming agents as well as potent NADPH-oxidase activators have been identified and characterized for human neutrophils. The cytokine tumour necrosis factor (TNF)-alpha is one prominent example of a priming agent and the synthetic hexaPeptide WKYMVm is an agonist that triggers an activation of the NADPH-oxidase of human neutrophils through two members of the Formyl Peptide family of Receptors, Formyl Peptide Receptor (FPR) and FPR-like 1 (FPRL1). This Peptide also activates murine neutrophils but the precise Receptor involved has not been previously characterized. We show in this study that WKYMVm activates stably transfected HL60 cells expressing murine Formyl Peptide Receptor-related sequence 2 (Fpr-rs2) and that activation of murine neutrophils with WKYMVm is blocked by an FPRL1-specific antagonist. WKYMVm is thus an agonist for Fpr-rs2 and we suggest that this Receptor is in fact the mouse orthologue of FPRL1. In addition, we show that the WKYMVm response in murine neutrophils can be primed by TNF-alpha and this priming process involves mobilization of subcellular granules. The results obtained using neutrophils derived from TNF Receptor type I (TNFRI)-deficient animals suggest that TNF-alpha exerts its priming effect via the TNFRI.
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Serum amyloid A mediates human neutrophil production of reactive oxygen species through a Receptor independent of Formyl Peptide Receptor like-1.
Journal of Leukocyte Biology, 2008Co-Authors: Lena Björkman, Francois Boulay, Jennie Karlsson, Marie-josèphe Rabiet, Johan Bylund, Anna Karlsson, Claes DahlgrenAbstract:Serum amyloid A (SAA) is one of the acute-phase reactants, a group of plasma proteins that increases immensely in concentration during microbial infections and inflammatory conditions, and a close relationship between SAA levels and disease activity in rheumatoid arthritis (RA) has been observed. RA is an inflammatory disease, where neutrophils play important roles, and SAA is thought to participate in the inflammatory reaction by being a neutrophil chemoattractant and inducer of proinflammatory cytokines. The biological effects of SAA are reportedly mediated mainly through Formyl Peptide Receptor like-1 (FPRL1), a G protein-coupled Receptor (GPCR) belonging to the Formyl Peptide Receptor family. Here, we confirmed the affinity of SAA for FPRL1 by showing that stably transfected HL-60 cells expressing FPRL1 were activated by SAA and that the response was inhibited by the use of the FPRL1-specific antagonist WRWWWW (WRW4). We also show that SAA activates the neutrophil NADPH-oxidase and that a reserve pool of Receptors is present in storage organelles mobilized by priming agents such as TNF-alpha and LPS from Gram-negative bacteria. The induced activity was inhibited by pertussis toxin, indicating the involvement of a GPCR. However, based on FPRL1-specific desensitization and use of FPRL1 antagonist WRW4, we found the SAA-mediated effects in neutrophils to be independent of FPRL1. Based on these findings, we conclude that SAA signaling in neutrophils is mediated through a GPCR, distinct from FPRL1. Future identification and characterization of the SAA Receptor could lead to development of novel, therapeutic targets for treatment of RA.
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Cyclosporin H, Boc-MLF and Boc-FLFLF are Antagonists that Preferentially Inhibit Activity Triggered Through the Formyl Peptide Receptor
Inflammation, 2007Co-Authors: Annalena Stenfeldt, Christine Wenneras, Huamei Fu, Jennie Karlsson, Johan Bylund, Claes DahlgrenAbstract:In order to properly interpret Receptor inhibition experiments, the precise Receptor specificities of the employed antagonists are of crucial importance. Lately, a great number of agonists for various Formyl Peptide Receptors have been identified using a selection of antagonists. However, some confusion exists as to the precise Receptor specificities of many of these antagonists. We have investigated the effects of Formyl Peptide Receptor family antagonists on the neutrophil response induced by agonists for the Formyl Peptide Receptor (FPR) and the Formyl Peptide Receptor like 1 (FPRL1). To determine FPR- and FPRL1-specific interactions, these antagonists should not be used at used at concentrations above 10 μM. Signaling through FPR was inhibited by low concentrations of the antagonists cyclosporin H, Boc-MLF (also termed Boc-1), and Boc-FLFLFL (also termed Boc-2), while higher concentrations also partly inhibited the signaling through FPRL1. The antagonist WRWWWW (WRW_4) specifically inhibited the signaling through FPRL1 at low concentrations but at high concentrations also partly the signaling through FPR. Based on the difference in potency of cyclosporin H and the two Boc-Peptides, we suggest using cyclosporin H as a specific inhibitor for FPR. To specifically inhibit the FPRL1 response the antagonist WRW_4 should be used.
Jae-sam Hwang - One of the best experts on this subject based on the ideXlab platform.
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A novel antimicrobial Peptide acting via Formyl Peptide Receptor 2 shows therapeutic effects against rheumatoid arthritis
Nature Publishing Group, 2018Co-Authors: Yoo Jung Park, Jae-sam Hwang, Ha Young Lee, Byunghyun Park, Mingyu Lee, Yu Sun Jeong, Dong Hyun Sohn, Jason Jungsik Song, Joon Ha Lee, Yoe-sik BaeAbstract:Abstract In oriental medicine, centipede Scolopendra subspinipes mutilans has long been used as a remedy for rheumatoid arthritis (RA), a well-known chronic autoimmune disorder. However, the molecular identities of its bioactive components have not yet been extensively investigated. We sought to identify bioactive molecules that control RA with a centipede. A novel antimicrobial Peptide (AMP) (scolopendrasin IX) was identified from Scolopendra subspinipes mutilans. Scolopendrasin IX markedly activated mouse neutrophils, by enhancing cytosolic calcium increase, chemotactic cellular migration, and generation of superoxide anion in neutrophils. As a target Receptor for scolopendrasin IX, Formyl Peptide Receptor (FPR)2 mediates neutrophil activation induced by the AMP. Furthermore, scolopendrasin IX administration strongly blocked the clinical phenotype of RA in an autoantibody-injected model. Mechanistically, the novel AMP inhibited inflammatory cytokine synthesis from the joints and neutrophil recruitment into the joint area. Collectively, we suggest that scolopendrasin IX is a novel potential therapeutic agent for the control of RA via FPR2
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a novel antimicrobial Peptide isolated from centipede scolopendra subspinipes mutilans stimulates neutrophil activity through Formyl Peptide Receptor 2
Biochemical and Biophysical Research Communications, 2017Co-Authors: Yoo Jung Park, Jae-sam HwangAbstract:Abstract In this study, we identified scolopendrasin X, a novel antimicrobial Peptide (AMP), from centipede Scolopendra subspinipes mutilans . 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.
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antimicrobial Peptide scolopendrasin vii derived from the centipede scolopendra subspinipes mutilans stimulates macrophage chemotaxis via Formyl Peptide Receptor 1
Journal of Biochemistry and Molecular Biology, 2015Co-Authors: Yoo Jung Park, Young Su Jung, Joon-seong Park, Jae-sam HwangAbstract:In this study, we report that one of the antimicrobial Peptides scolopendrasin VII, derived from Scolopendra subspinipes mutilans, stimulates actin polymerization and the subsequent chemotactic migration of macrophages through the activation of ERK and protein kinase B (Akt) activity. The scolopendrasin VII-induced chemotactic migration of macrophages is inhibited by the Formyl Peptide Receptor 1 (FPR1) antagonist cyclosporine H. We also found that scolopendrasin VII stimulate the chemotactic migration of FPR1-transfected RBL-2H3 cells, but not that of vector-transfected cells; moreover, scolopendrasin VII directly binds to FPR1. Our findings therefore suggest that the antimicrobial Peptide scolopendrasin VII, derived from Scolopendra subspinipes mutilans, stimulates macrophages, resulting in chemotactic migration via FPR1 signaling, and the Peptide can be useful in the study of FPR1-related biological responses. [BMB Reports 2015; 48(8): 479-484]
Ha Young Lee - One of the best experts on this subject based on the ideXlab platform.
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A novel antimicrobial Peptide acting via Formyl Peptide Receptor 2 shows therapeutic effects against rheumatoid arthritis
Nature Publishing Group, 2018Co-Authors: Yoo Jung Park, Jae-sam Hwang, Ha Young Lee, Byunghyun Park, Mingyu Lee, Yu Sun Jeong, Dong Hyun Sohn, Jason Jungsik Song, Joon Ha Lee, Yoe-sik BaeAbstract:Abstract In oriental medicine, centipede Scolopendra subspinipes mutilans has long been used as a remedy for rheumatoid arthritis (RA), a well-known chronic autoimmune disorder. However, the molecular identities of its bioactive components have not yet been extensively investigated. We sought to identify bioactive molecules that control RA with a centipede. A novel antimicrobial Peptide (AMP) (scolopendrasin IX) was identified from Scolopendra subspinipes mutilans. Scolopendrasin IX markedly activated mouse neutrophils, by enhancing cytosolic calcium increase, chemotactic cellular migration, and generation of superoxide anion in neutrophils. As a target Receptor for scolopendrasin IX, Formyl Peptide Receptor (FPR)2 mediates neutrophil activation induced by the AMP. Furthermore, scolopendrasin IX administration strongly blocked the clinical phenotype of RA in an autoantibody-injected model. Mechanistically, the novel AMP inhibited inflammatory cytokine synthesis from the joints and neutrophil recruitment into the joint area. Collectively, we suggest that scolopendrasin IX is a novel potential therapeutic agent for the control of RA via FPR2
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fam19a5 a brain specific chemokine inhibits rankl induced osteoclast formation through Formyl Peptide Receptor 2
Scientific Reports, 2017Co-Authors: Min Young Park, Ha Young Lee, Byunghyun Park, Mingyu Lee, Hyung Sik Kim, Eun Bee Cho, Jae Young Seong, Yoe-sik BaeAbstract:Osteoclasts can be differentiated from bone marrow-derived macrophages (BMDM). They play a key role in bone resorption. Identifying novel molecules that can regulate osteoclastogenesis has been an important issue. In this study, we found that FAM19A5, a neurokine or brain-specific chemokine, strongly stimulated mouse BMDM, resulting in chemotactic migration and inhibition of RANKL-induced osteoclastogenesis. Expression levels of osteoclast-related genes such as RANK, TRAF6, OSCAR, TRAP, Blimp1, c-fos, and NFATc1 were markedly decreased by FAM19A5. However, negative regulators of osteoclastogenesis such as MafB and IRF-8 were upregulated by FAM19A5. FAM19A5 also downregulated expression levels of RANKL-induced fusogenic genes such as OC-STAMP, DC-STAMP, and Atp6v0d2. FAM19A5-induced inhibitory effect on osteoclastogenesis was significantly reversed by a Formyl Peptide Receptor (FPR) 2 antagonist WRW4 or by FPR2-deficiency, suggesting a crucial role of FPR2 in the regulation of osteoclastogenesis. Collectively, our results suggest that FAM19A5 and its target Receptor FPR2 can act as novel endogenous ligand/Receptor to negatively regulate osteoclastogenesis. They might be regarded as potential targets to control osteoclast formation and bone disorders.
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Activation of human monocytes by a Formyl Peptide Receptor 2-derived pepducin.
FEBS letters, 2010Co-Authors: Ha Young Lee, Joon-seong Park, Sang Doo Kim, Jae Woong Shim, Hak Jung Kim, Jae Young Kwon, Jong-min Kim, Suk-hwan Baek, Yoe-sik BaeAbstract:We synthesized and investigated the effect of Formyl Peptide Receptor 2 (FPR2)-derived pepducins in human monocytes. The FPR2-based cell-penetrating lipoPeptide, "pepducin" (F2pal-16), stimulated intracellular calcium increase in human monocytes via pertussis toxin (PTX)-sensitive G-protein and phospholipase C (PLC) activity. From a functional aspect, we showed that F2pal-16 stimulated monocyte chemotaxis. F2pal-16 also stimulated the generation of superoxide anion in human monocytes. Moreover, F2pal-16 dramatically increased the production of several kinds of pro-inflammatory cytokines (CXCL8, CCL2, IL-1β and TNF-α) in human monocytes via NF-κB activation. Since FPR2 plays an important role in immune responses, F2pal-16 can serve as a useful reagent for the study of FPR2-mediated immune modulation.
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the synthetic Peptide trp lys tyr met val d met inhibits human monocyte derived dendritic cell maturation via Formyl Peptide Receptor and Formyl Peptide Receptor like 2
Journal of Immunology, 2005Co-Authors: Hyun Kyu Kang, Ha Young Lee, Mikyoung Kim, Kyoung Sun Park, Yeong Min Park, Jongyoung Kwak, Yoe-sik BaeAbstract:Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm) has been reported to stimulate monocytes, neutrophils, and dendritic cells (DCs). However, although WKYMVm has been reported to function as a DC chemoattractant, its role on DC maturation has not been examined. In this study, we investigated the effects of WKYMVm on human DC maturation. The costimulation of DCs with WKYMVm and LPS dramatically inhibited LPS-induced IL-12 production, CD86 and HLA-DR surface expression, and DC-mediated T cell proliferation. However, DC phagocytic activity was increased by WKYMVm stimulation. These findings demonstrate that WKYMVm inhibits DC maturation by LPS. In terms of the mechanism underlying DC maturation inhibition by WKYMVm, we found that LPS-induced DC maturation was negatively regulated by WKYMVm-stimulated ERK activity. Moreover, the costimulation of DCs with WKYMVm and LPS dramatically inhibited the LPS-induced accumulations of IL-12 mRNA, thus suggesting that WKYMVm inhibits LPS-induced IL-12 production at the transcriptional level. We also found that DCs express two WKYMVm Receptors, Formyl Peptide Receptor (FPR) and FPR-like 2 (FPRL2). In addition, Formyl-Met-Leu-Phe (a FPR ligand), Trp-Lys-Tyr-Met-Val-Met, Hp(2-20) Peptide, and F2L (three FPRL2 ligands) inhibited LPS-induced IL-12 production in DCs. Taken together, our findings indicate that the activations of FPR and FPRL2 inhibit LPS-induced DC maturation, and suggest that these two Receptors should be regarded as important potential therapeutic targets for the modulation of DC maturation.
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identification of Peptides that antagonize Formyl Peptide Receptor like 1 mediated signaling
Journal of Immunology, 2004Co-Authors: Yoe-sik Bae, Ha Young Lee, Hyun Kyu Kang, Jongyoung Kwak, Jung Im Kim, Sung Ho RyuAbstract:Formyl Peptide Receptor-like 1 (FPRL1) is an important classical chemoattractant Receptor that is expressed in phagocytic cells in the peripheral blood and brain. Recently, various novel agonists have been identified from several origins, such as host-derived molecules. Activation of FPRL1 is closely related to inflammatory responses in the host defense mechanism and neurodegenerative disorders. In the present study we identified several novel Peptides by screening hexaPeptide libraries that inhibit the binding of one of FPRL1’s agonists (Trp-Lys-Tyr-Met-Val-d-Met-CONH 2 (WKYMVm)) to its specific Receptor, FPRL1, in RBL-2H3 cells. Among the novel Peptides, Trp-Arg-Trp-Trp-Trp-Trp-CONH 2 (WRWWWW (WRW 4 )) showed the most potent activity in terms of inhibiting WKYMVm binding to FPRL1. We also found that WRW 4 inhibited the activation of FPRL1 by WKYMVm, resulting in the complete inhibition of the intracellular calcium increase, extracellular signal-regulated kinase activation, and chemotactic migration of cells toward WKYMVm. For the Receptor specificity of WRW 4 to the FPR family, we observed that WRW 4 specifically inhibit the increase in intracellular calcium by the FPRL1 agonists MMK-1, amyloid β42 (Aβ42) Peptide, and F Peptide, but not by the FPR agonist, fMLF. To investigate the effect of WRW 4 on endogenous FPRL1 ligand-induced cellular responses, we examined its effect on Aβ42 Peptide in human neutrophils. Aβ42 Peptide-induced superoxide generation and chemotactic migration of neutrophils were inhibited by WRW 4 , which also completely inhibited the internalization of Aβ42 Peptide in human macrophages. WRW 4 is the first specific FPRL1 antagonist and is expected to be useful in the study of FPRL1 signaling and in the development of drugs against FPRL1-related diseases.