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dc.contributor.authorAragoneses-Fenoll, Laura 
dc.contributor.authorMontes-Casado, Maria 
dc.contributor.authorOjeda, Gloria 
dc.contributor.authorAcosta, Y Y
dc.contributor.authorHerranz, J
dc.contributor.authorMartinez, Sonia 
dc.contributor.authorBlanco-Aparicio, Carmen 
dc.contributor.authorCriado, G
dc.contributor.authorPastor Fernández, Joaquín 
dc.contributor.authorDianzani, U
dc.contributor.authorPortoles, Pilar 
dc.contributor.authorRojo, J M
dc.date.accessioned2020-06-02T07:14:48Z
dc.date.available2020-06-02T07:14:48Z
dc.date.issued2016-04-15
dc.identifier.citationBiochem Pharmacol. 2016 Apr 15;106:56-69.es_ES
dc.identifier.issn0006-2952es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/10246
dc.description.abstractClass IA phosphoinositide 3-kinases (PI3Ks) are essential to function of normal and tumor cells, and to modulate immune responses. T lymphocytes express high levels of p110α and p110δ class IA PI3K. Whereas the functioning of PI3K p110δ in immune and autoimmune reactions is well established, the role of p110α is less well understood. Here, a novel dual p110α/δ inhibitor (ETP-46321) and highly specific p110α (A66) or p110δ (IC87114) inhibitors have been compared concerning T cell activation in vitro, as well as the effect on responses to protein antigen and collagen-induced arthritis in vivo. In vitro activation of naive CD4(+) T lymphocytes by anti-CD3 and anti-CD28 was inhibited more effectively by the p110δ inhibitor than by the p110α inhibitor as measured by cytokine secretion (IL-2, IL-10, and IFN-γ), T-bet expression and NFAT activation. In activated CD4(+) T cells re-stimulated through CD3 and ICOS, IC87114 inhibited Akt and Erk activation, and the secretion of IL-2, IL-4, IL-17A, and IFN-γ better than A66. The p110α/δ inhibitor ETP-46321, or p110α plus p110δ inhibitors also inhibited IL-21 secretion by differentiated CD4(+) T follicular (Tfh) or IL-17-producing (Th17) helper cells. In vivo, therapeutic administration of ETP-46321 significantly inhibited responses to protein antigen as well as collagen-induced arthritis, as measured by antigen-specific antibody responses, secretion of IL-10, IL-17A or IFN-γ, or clinical symptoms. Hence, p110α as well as p110δ Class IA PI3Ks are important to immune regulation; inhibition of both subunits may be an effective therapeutic approach in inflammatory autoimmune diseases like rheumatoid arthritis.es_ES
dc.description.sponsorshipP.P. is a Tenured Scientist of the Consejo Superior de Investigaciones Científicas (CSIC) at the Centro Nacional de Microbiología, Instituto de Salud Carlos III. GC is recipient of a Miguel Servet fellowship(CPII13/0014). YYA is recipient of a PredoctoralFellowship of the “Junta de Ampliación de Estudios” (JAE) Program (CSIC, Ministerio de Economía y Competitividad, Spain).Supported by Grants PI13/01809 (to JMR), PI13/02153 (to PP)and PI11/00028 (toGC) from “Acción Estratégica en Salud, Plan Estatal I+D+i”, Ministerio de Economía y Competitividad (MINECO), Spain; by Grants CIT-090100-2007-48 (Ministerio de Ciencia y Tecnología) and ADE08/90038 (Ministerio de Sanidad, Igualdad y Servicios Sociales) to JP; and by Associazione Italiana Ricerca sul Cancro grant IG14430(AIRC, Milan) and Fondazione Amici di Jean (Turin) to UD.es_ES
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.relation.isversionofPostprintes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectA-66es_ES
dc.subjectCD28es_ES
dc.subjectETP-46321es_ES
dc.subjectIC-87114es_ES
dc.subjectICOSes_ES
dc.subjectPI3K inhibitorses_ES
dc.subjectPhosphatidyl inositol-3 kinasees_ES
dc.subjectRheumatoid arthritises_ES
dc.subjectT lymphocyteses_ES
dc.subject.meshAnimalses_ES
dc.subject.meshAntibodieses_ES
dc.subject.meshArthritis, Experimentales_ES
dc.subject.meshCD28 Antigenses_ES
dc.subject.meshCD3 Complexes_ES
dc.subject.meshCD4-Positive T-Lymphocyteses_ES
dc.subject.meshClass Ia Phosphatidylinositol 3-Kinasees_ES
dc.subject.meshEnzyme Inhibitorses_ES
dc.subject.meshExtracellular Signal-Regulated MAP Kinaseses_ES
dc.subject.meshGene Expressiones_ES
dc.subject.meshImidazoleses_ES
dc.subject.meshInterferon-gammaes_ES
dc.subject.meshInterleukin-10es_ES
dc.subject.meshInterleukin-2es_ES
dc.subject.meshLymph Nodeses_ES
dc.subject.meshLymphocyte Activationes_ES
dc.subject.meshMicees_ES
dc.subject.meshMice, Inbred C57BLes_ES
dc.subject.meshNFATC Transcription Factorses_ES
dc.subject.meshProtein Subunitses_ES
dc.subject.meshProto-Oncogene Proteins c-aktes_ES
dc.subject.meshPyrazineses_ES
dc.subject.meshT-Box Domain Proteinses_ES
dc.subject.meshPhosphoinositide-3 Kinase Inhibitorses_ES
dc.titleETP-46321, a dual p110α/δ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritises_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución-NoComercial-SinObraDerivada 4.0 Internacional*
dc.identifier.pubmedID26883061es_ES
dc.format.volume106es_ES
dc.format.page56-69es_ES
dc.identifier.doi10.1016/j.bcp.2016.02.005es_ES
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderMinisterio de Ciencia y Tecnología (España)es_ES
dc.contributor.funderMinisterio de Sanidad, Servicios Sociales e Igualdad (España)es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1873-2968es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.bcp.2016.02.005es_ES
dc.identifier.journalBiochemical pharmacologyes_ES
dc.repisalud.centroISCIII::Centro Nacional de Microbiologíaes_ES
dc.repisalud.institucionISCIIIes_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/CPII13/0014es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/PI13/01809es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/PI13/02153es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/PI11/00028es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/CIT-090100-2007-48es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/ADE08/90038es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/IG14430es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Atribución-NoComercial-SinObraDerivada 4.0 Internacional
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