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...
| Autores: | ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artículo |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Lenguaje: | Inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/17283 |
| Acceso en línea: | http://hdl.handle.net/20.500.12105/17283 |
| Nivel de acceso: | 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 |
| _version_ | 1878734993996382208 |
|---|---|
| author | Hurtado-Guerrero, Isaac |
| 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 |
| author_browse | Fernández, Óscar Guerrero, Miguel Hurtado-Guerrero, Isaac Leyva, Laura León, Antonio Oliver-Martos, Begoña Pinto-Medel, María Jesús Rodriguez-Bada, Jose Luis Urbaneja, Patricia |
| 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 |
| collection | Repisalud |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_73e00a5090621ecee64b981cdeeb86a2 |
| institution | Instituto de Salud Carlos III (ISCIII) |
| instname_str | Instituto de Salud Carlos III (ISCIII) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repisalud.isciii.es:20.500.12105/17283 |
| publishDate | 2017 |
| publishDateSort | 2017 |
| publisher | Public Library of Science (PLOS) |
| publisherStr | Public Library of Science (PLOS) |
| reponame_str | Repisalud |
| spelling | 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 Pinto-Medel, María Jesús Urbaneja, Patricia Rodriguez-Bada, Jose Luis León, Antonio Guerrero, Miguel Fernández, Óscar Leyva, Laura Oliver-Martos, Begoña 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 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. Public Library of Science (PLOS) http://hdl.handle.net/20.500.12105/17283 |
| 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 | 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_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_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 |
| 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 |
| topic_facet | 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 |
| url | http://hdl.handle.net/20.500.12105/17283 |