Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß

Interferon beta (IFNß) is a common treatment used for multiple sclerosis (MS) which acts through the activation of the JAK-STAT pathway. However, this therapy is not always effective and currently there are no reliable biomarkers to predict therapeutic response. We postulate that the heterogeneity i...

Descripción completa

Detalles Bibliográficos
Autores: Hurtado-Guerrero, Isaac, Pinto-Medel, María Jesús, Urbaneja, Patricia, Rodriguez-Bada, Jose Luis, León, Antonio, Guerrero, Miguel, Fernández, Óscar, Leyva, Laura, Oliver-Martos, Begoña
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17283
Acceso en línea:http://hdl.handle.net/20.500.12105/17283
Access Level:acceso abierto
Palabra clave:Biomarcadores
Citometría de flujo
Humanos
Leucocitos mononucleares
Monocitos
Esclerosis múltiple
Fenotipo
Factor de Transcripción STAT1
Factor de Transcripción STAT2
Resultado del tratamiento
Biomarkers
Flow Cytometry
Humans
Interferon beta-1a
Interferon-beta
Leukocytes, Mononuclear
Monocytes
Multiple Sclerosis
Phenotype
STAT1 Transcription Factor
STAT2 Transcription Factor
Treatment Outcome
id ES_73e00a5090621ecee64b981cdeeb86a2
oai_identifier_str oai:repisalud.isciii.es:20.500.12105/17283
network_acronym_str ES
network_name_str España
repository_id_str
spelling Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNßHurtado-Guerrero, IsaacPinto-Medel, María JesúsUrbaneja, PatriciaRodriguez-Bada, Jose LuisLeón, AntonioGuerrero, MiguelFernández, ÓscarLeyva, LauraOliver-Martos, BegoñaBiomarcadoresCitometría de flujoHumanosLeucocitos mononuclearesMonocitosEsclerosis múltipleFenotipoFactor de Transcripción STAT1Factor de Transcripción STAT2Resultado del tratamientoBiomarkersFlow CytometryHumansInterferon beta-1aInterferon-betaLeukocytes, MononuclearMonocytesMultiple SclerosisPhenotypeSTAT1 Transcription FactorSTAT2 Transcription FactorTreatment OutcomeInterferon beta (IFNß) is a common treatment used for multiple sclerosis (MS) which acts through the activation of the JAK-STAT pathway. However, this therapy is not always effective and currently there are no reliable biomarkers to predict therapeutic response. We postulate that the heterogeneity in the response to IFNß therapy could be related to differential activation patterns of the JAK-STAT signaling pathway. Our aim was to evaluate the basal levels and the short term activation of this pathway after IFNß stimulation in untreated and IFNß treated patients, as well as according to therapeutic response. Therefore, cell surface levels of IFNAR subunits (IFNAR1 and IFNAR2) and the activated forms of STAT1 and STAT2 were assessed in peripheral blood mononuclear cells from MS patients by flow cytometry. Basal levels of each of the markers strongly correlated with the expression of the others in untreated patients, but many of these correlations lost significance in treated patients and after short term activation with IFNß. Patients who had undergone IFNß treatment showed higher basal levels of IFNAR1 and pSTAT1, but a reduced response to in vitro exposure to IFNß. Conversely, untreated patients, with lower basal levels, showed a greater ability of short term activation of this pathway. Monocytes from responder patients had lower IFNAR1 levels (p = 0.039) and higher IFNAR2 levels (p = 0.035) than non-responders just after IFNß stimulation. A cluster analysis showed that levels of IFNAR1, IFNAR2 and pSTAT1-2 in monocytes grouped 13 out of 19 responder patients with a similar expression pattern, showing an association of this pattern with the phenotype of good response to IFNß (p = 0.013). Our findings suggest that an activation pattern of the IFNß signaling pathway in monocytes could be associated with a clinical phenotype of good response to IFNß treatment and that a differential modulation of the IFNAR subunits in monocytes could be related with treatment effectiveness.Public Library of Science (PLOS)Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.20242024-01-2320172017-01-1920172017-01-19research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/17283reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttps://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/172832026-06-12T12:43:37Z
dc.title.none.fl_str_mv Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß
title Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß
spellingShingle Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß
Hurtado-Guerrero, Isaac
Biomarcadores
Citometría de flujo
Humanos
Leucocitos mononucleares
Monocitos
Esclerosis múltiple
Fenotipo
Factor de Transcripción STAT1
Factor de Transcripción STAT2
Resultado del tratamiento
Biomarkers
Flow Cytometry
Humans
Interferon beta-1a
Interferon-beta
Leukocytes, Mononuclear
Monocytes
Multiple Sclerosis
Phenotype
STAT1 Transcription Factor
STAT2 Transcription Factor
Treatment Outcome
title_short Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß
title_full Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß
title_fullStr Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß
title_full_unstemmed Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß
title_sort Activation of the JAK-STAT Signaling Pathway after In Vitro Stimulation with IFNß in Multiple Sclerosis Patients According to the Therapeutic Response to IFNß
dc.creator.none.fl_str_mv Hurtado-Guerrero, Isaac
Pinto-Medel, María Jesús
Urbaneja, Patricia
Rodriguez-Bada, Jose Luis
León, Antonio
Guerrero, Miguel
Fernández, Óscar
Leyva, Laura
Oliver-Martos, Begoña
author Hurtado-Guerrero, Isaac
author_facet Hurtado-Guerrero, Isaac
Pinto-Medel, María Jesús
Urbaneja, Patricia
Rodriguez-Bada, Jose Luis
León, Antonio
Guerrero, Miguel
Fernández, Óscar
Leyva, Laura
Oliver-Martos, Begoña
author_role author
author2 Pinto-Medel, María Jesús
Urbaneja, Patricia
Rodriguez-Bada, Jose Luis
León, Antonio
Guerrero, Miguel
Fernández, Óscar
Leyva, Laura
Oliver-Martos, Begoña
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.
dc.subject.none.fl_str_mv Biomarcadores
Citometría de flujo
Humanos
Leucocitos mononucleares
Monocitos
Esclerosis múltiple
Fenotipo
Factor de Transcripción STAT1
Factor de Transcripción STAT2
Resultado del tratamiento
Biomarkers
Flow Cytometry
Humans
Interferon beta-1a
Interferon-beta
Leukocytes, Mononuclear
Monocytes
Multiple Sclerosis
Phenotype
STAT1 Transcription Factor
STAT2 Transcription Factor
Treatment Outcome
topic Biomarcadores
Citometría de flujo
Humanos
Leucocitos mononucleares
Monocitos
Esclerosis múltiple
Fenotipo
Factor de Transcripción STAT1
Factor de Transcripción STAT2
Resultado del tratamiento
Biomarkers
Flow Cytometry
Humans
Interferon beta-1a
Interferon-beta
Leukocytes, Mononuclear
Monocytes
Multiple Sclerosis
Phenotype
STAT1 Transcription Factor
STAT2 Transcription Factor
Treatment Outcome
description Interferon beta (IFNß) is a common treatment used for multiple sclerosis (MS) which acts through the activation of the JAK-STAT pathway. However, this therapy is not always effective and currently there are no reliable biomarkers to predict therapeutic response. We postulate that the heterogeneity in the response to IFNß therapy could be related to differential activation patterns of the JAK-STAT signaling pathway. Our aim was to evaluate the basal levels and the short term activation of this pathway after IFNß stimulation in untreated and IFNß treated patients, as well as according to therapeutic response. Therefore, cell surface levels of IFNAR subunits (IFNAR1 and IFNAR2) and the activated forms of STAT1 and STAT2 were assessed in peripheral blood mononuclear cells from MS patients by flow cytometry. Basal levels of each of the markers strongly correlated with the expression of the others in untreated patients, but many of these correlations lost significance in treated patients and after short term activation with IFNß. Patients who had undergone IFNß treatment showed higher basal levels of IFNAR1 and pSTAT1, but a reduced response to in vitro exposure to IFNß. Conversely, untreated patients, with lower basal levels, showed a greater ability of short term activation of this pathway. Monocytes from responder patients had lower IFNAR1 levels (p = 0.039) and higher IFNAR2 levels (p = 0.035) than non-responders just after IFNß stimulation. A cluster analysis showed that levels of IFNAR1, IFNAR2 and pSTAT1-2 in monocytes grouped 13 out of 19 responder patients with a similar expression pattern, showing an association of this pattern with the phenotype of good response to IFNß (p = 0.013). Our findings suggest that an activation pattern of the IFNß signaling pathway in monocytes could be associated with a clinical phenotype of good response to IFNß treatment and that a differential modulation of the IFNAR subunits in monocytes could be related with treatment effectiveness.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017-01-19
2017
2017-01-19
2024
2024-01-23
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/17283
url http://hdl.handle.net/20.500.12105/17283
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Public Library of Science (PLOS)
publisher.none.fl_str_mv Public Library of Science (PLOS)
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869410841618546688
score 15,81155

Similares en LA Referencia