Enhanced immunostimulatory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpG

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dc.citation.epage1179en_US
dc.citation.issueNumber4en_US
dc.citation.spage1170en_US
dc.citation.volumeNumber45en_US
dc.contributor.authorYildiz, S.en_US
dc.contributor.authorAlpdundar, E.en_US
dc.contributor.authorGungor, B.en_US
dc.contributor.authorKahraman, T.en_US
dc.contributor.authorBayyurt, B.en_US
dc.contributor.authorGursel, I.en_US
dc.contributor.authorGursel, M.en_US
dc.date.accessioned2016-02-08T10:22:47Z
dc.date.available2016-02-08T10:22:47Z
dc.date.issued2015en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractRecognition of pathogen-derived nucleic acids by immune cells is critical for the activation of protective innate immune responses. Bacterial cyclic dinucleotides (CDNs) are small nucleic acids that are directly recognized by the cytosolic DNA sensor STING (stimulator of IFN genes), initiating a response characterized by proinflammatory cytokine and type I IFN production. Strategies to improve the immune stimulatory activities of CDNs can further their potential for clinical development. Here, we demonstrate that a simple complex of cylic-di-GMP with a cell-penetrating peptide enhances both cellular delivery and biological activity of the cyclic-di-GMP in murine splenocytes. Furthermore, our findings establish that activation of the TLR-dependent and TLR-independent DNA recognition pathways through combined use of CpG oligonucleotide (ODN) and CDN results in synergistic activity, augmenting cytokine production (IFN-α/β, IL-6, TNF-α, IP-10), costimulatory molecule upregulation (MHC class II, CD86), and antigen-specific humoral and cellular immunity. Results presented herein indicate that 3′3′-cGAMP, a recently identified bacterial CDN, is a superior stimulator of IFN genes ligand than cyclic-di-GMP in human PBMCs. Collectively, these findings suggest that the immune-stimulatory properties of CDNs can be augmented through peptide complexation or synergistic use with CpG oligonucleotide and may be of interest for the development of CDN-based immunotherapeutic agents.en_US
dc.identifier.doi10.1002/eji.201445133en_US
dc.identifier.issn0014-2980
dc.identifier.urihttp://hdl.handle.net/11693/24013en_US
dc.language.isoEnglishen_US
dc.publisherWiley - V C H Verlag GmbH & Co. KGaAen_US
dc.relation.isversionofhttp://dx.doi.org/10.1002/eji.201445133en_US
dc.source.titleEuropean Journal of Immunologyen_US
dc.subjectArginine peptide (nona-arginine)en_US
dc.subjectCGAMPen_US
dc.subjectCpG ODNen_US
dc.subjectCyclic-di-GMPen_US
dc.subjectImmunostimulationen_US
dc.subjectAlpha interferonen_US
dc.subjectArginineen_US
dc.subjectBacterial proteinen_US
dc.subjectBeta interferonen_US
dc.subjectCD11b antigenen_US
dc.subjectCD14 antigenen_US
dc.subjectCD45 antigenen_US
dc.subjectCD86 antigenen_US
dc.subjectCell penetrating peptideen_US
dc.subjectCpG oligodeoxynucleotideen_US
dc.subjectCyclic diguanosine monophosphateen_US
dc.subjectDinucleotideen_US
dc.subjectDNAen_US
dc.subjectFluorescent dyeen_US
dc.subjectGamma interferon inducible protein 10en_US
dc.subjectGlycoprotein p 15095en_US
dc.subjectImmunostimulating agenten_US
dc.subjectInterferonen_US
dc.subjectInterleukin 12en_US
dc.subjectInterleukin 6en_US
dc.subjectLipofectamineen_US
dc.subjectMajor histocompatibility antigen class 2en_US
dc.subjectOvalbuminen_US
dc.subjectToll like receptor 9en_US
dc.subjectTrypan blueen_US
dc.subjectTumor necrosis factor alphaen_US
dc.subjectUnclassified drugen_US
dc.subjectBis(3',5')-cyclic diguanylic aciden_US
dc.subjectCell penetrating peptideen_US
dc.subjectCPG-oligonucleotideen_US
dc.subjectCyclic GMPen_US
dc.subjectCyclic guanosine monophosphate-adenosine monophosphateen_US
dc.subjectCyclic nucleotideen_US
dc.subjectCytokineen_US
dc.subjectImmunological adjuvanten_US
dc.subjectInterferonen_US
dc.subjectMembrane proteinen_US
dc.subjectMPYS protein, mouseen_US
dc.subjectOligodeoxyribonucleotideen_US
dc.subjectPeptideen_US
dc.subjectAnimal cellen_US
dc.subjectAnimal experimenten_US
dc.subjectAnimal modelen_US
dc.subjectAntigen presenting cellen_US
dc.subjectArticleen_US
dc.subjectCell maturationen_US
dc.subjectCellular immunityen_US
dc.subjectComplex formationen_US
dc.subjectControlled studyen_US
dc.subjectCytokine productionen_US
dc.subjectCytokine releaseen_US
dc.subjectDrug potentiationen_US
dc.subjectHumanen_US
dc.subjectHuman cellen_US
dc.subjectImmunostimulationen_US
dc.subjectInnate immunityen_US
dc.subjectInternalizationen_US
dc.subjectLow drug doseen_US
dc.subjectMouseen_US
dc.subjectNonhumanen_US
dc.subjectNormal humanen_US
dc.subjectPeripheral blood mononuclear cellen_US
dc.subjectPriority journalen_US
dc.subjectSpleen cellen_US
dc.subjectTumor volumeen_US
dc.subjectUpregulationen_US
dc.subjectAnalogs and derivativesen_US
dc.subjectAnimalen_US
dc.subjectBiosynthesisen_US
dc.subjectC57BL mouseen_US
dc.subjectChemistryen_US
dc.subjectCpG islanden_US
dc.subjectCytologyen_US
dc.subjectDrug effectsen_US
dc.subjectSpleenen_US
dc.subjectTumor cell cultureen_US
dc.subjectAdjuvants, Immunologicen_US
dc.subjectAnimalsen_US
dc.subjectCell-Penetrating Peptidesen_US
dc.subjectCpG Islandsen_US
dc.subjectCyclic GMPen_US
dc.subjectCytokinesen_US
dc.subjectHumansen_US
dc.subjectImmunity, Innateen_US
dc.subjectInterferon Type Ien_US
dc.subjectMembrane Proteinsen_US
dc.subjectMiceen_US
dc.subjectMice, Inbred C57BLen_US
dc.subjectNucleotides, Cyclicen_US
dc.subjectOligodeoxyribonucleotidesen_US
dc.subjectPeptidesen_US
dc.subjectSpleenen_US
dc.subjectTumor Cells, Cultureden_US
dc.titleEnhanced immunostimulatory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpGen_US
dc.typeArticleen_US

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