Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression
The IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and has been associated with demethylation of the intronic Conserved Non Coding Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controll...
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description | The IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and has been associated with demethylation of the intronic Conserved Non Coding Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway. |
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However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0153682</identifier><identifier>PMID: 27077371</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Biology and life sciences ; CD25 antigen ; Cellular signal transduction ; Conserved sequence ; Cycloheximide ; Demethylation ; DNA Methylation - drug effects ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Foxp3 protein ; Gene expression ; Gene Expression Regulation - drug effects ; Genetic aspects ; Human health and pathology ; Humans ; Immunology ; Immunoregulation ; Infectious diseases ; Interleukin 2 ; Introns - genetics ; Janus Kinase 3 - antagonists & inhibitors ; Janus Kinase 3 - metabolism ; Life Sciences ; Lymphocytes ; Lymphocytes T ; Medicine and health sciences ; Mice ; MicroRNAs ; Mutation ; Pharmacology ; Phosphorylation ; Physiological aspects ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Reduction ; Research and Analysis Methods ; Restoration ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Stat5 protein ; STAT5 Transcription Factor - metabolism ; T cells ; T-Lymphocytes, Regulatory - cytology ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - metabolism ; Transcription factors</subject><ispartof>PloS one, 2016-04, Vol.11 (4), p.e0153682-e0153682</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Goldstein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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drug effects</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Foxp3 protein</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Genetic aspects</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Immunology</topic><topic>Immunoregulation</topic><topic>Infectious diseases</topic><topic>Interleukin 2</topic><topic>Introns - genetics</topic><topic>Janus Kinase 3 - antagonists & inhibitors</topic><topic>Janus Kinase 3 - metabolism</topic><topic>Life Sciences</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Medicine and health sciences</topic><topic>Mice</topic><topic>MicroRNAs</topic><topic>Mutation</topic><topic>Pharmacology</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proteins</topic><topic>Reduction</topic><topic>Research and Analysis Methods</topic><topic>Restoration</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Stat5 protein</topic><topic>STAT5 Transcription Factor - metabolism</topic><topic>T cells</topic><topic>T-Lymphocytes, Regulatory - cytology</topic><topic>T-Lymphocytes, Regulatory - drug effects</topic><topic>T-Lymphocytes, Regulatory - metabolism</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Goldstein, Jérémie D</creatorcontrib><creatorcontrib>Burlion, Aude</creatorcontrib><creatorcontrib>Zaragoza, Bruno</creatorcontrib><creatorcontrib>Sendeyo, Kélhia</creatorcontrib><creatorcontrib>Polansky, Julia K</creatorcontrib><creatorcontrib>Huehn, Jochen</creatorcontrib><creatorcontrib>Piaggio, Eliane</creatorcontrib><creatorcontrib>Salomon, Benoit L</creatorcontrib><creatorcontrib>Marodon, Gilles</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27077371</pmid><doi>10.1371/journal.pone.0153682</doi><tpages>e0153682</tpages><orcidid>https://orcid.org/0000-0003-4889-6785</orcidid><orcidid>https://orcid.org/0000-0001-8071-1379</orcidid><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
subjects | Animals Biology and life sciences CD25 antigen Cellular signal transduction Conserved sequence Cycloheximide Demethylation DNA Methylation - drug effects Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Foxp3 protein Gene expression Gene Expression Regulation - drug effects Genetic aspects Human health and pathology Humans Immunology Immunoregulation Infectious diseases Interleukin 2 Introns - genetics Janus Kinase 3 - antagonists & inhibitors Janus Kinase 3 - metabolism Life Sciences Lymphocytes Lymphocytes T Medicine and health sciences Mice MicroRNAs Mutation Pharmacology Phosphorylation Physiological aspects Protein Kinase Inhibitors - pharmacology Proteins Reduction Research and Analysis Methods Restoration RNA, Messenger - genetics RNA, Messenger - metabolism Signal transduction Signal Transduction - drug effects Signaling Stat5 protein STAT5 Transcription Factor - metabolism T cells T-Lymphocytes, Regulatory - cytology T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - metabolism Transcription factors |
title | Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression |
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