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Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent
Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellular...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721755/ https://www.ncbi.nlm.nih.gov/pubmed/31443172 http://dx.doi.org/10.3390/cells8080898 |
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author | Alunno, Alessia Padjen, Ivan Fanouriakis, Antonis Boumpas, Dimitrios T. |
author_facet | Alunno, Alessia Padjen, Ivan Fanouriakis, Antonis Boumpas, Dimitrios T. |
author_sort | Alunno, Alessia |
collection | PubMed |
description | Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor. |
format | Online Article Text |
id | pubmed-6721755 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67217552019-09-10 Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent Alunno, Alessia Padjen, Ivan Fanouriakis, Antonis Boumpas, Dimitrios T. Cells Review Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor. MDPI 2019-08-15 /pmc/articles/PMC6721755/ /pubmed/31443172 http://dx.doi.org/10.3390/cells8080898 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Alunno, Alessia Padjen, Ivan Fanouriakis, Antonis Boumpas, Dimitrios T. Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent |
title | Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent |
title_full | Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent |
title_fullStr | Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent |
title_full_unstemmed | Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent |
title_short | Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus: Integration of Distinct Inflammatory Pathways and the Prospect of Their Inhibition with an Oral Agent |
title_sort | pathogenic and therapeutic relevance of jak/stat signaling in systemic lupus erythematosus: integration of distinct inflammatory pathways and the prospect of their inhibition with an oral agent |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721755/ https://www.ncbi.nlm.nih.gov/pubmed/31443172 http://dx.doi.org/10.3390/cells8080898 |
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