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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

1
Rheumatology Unit, Department of Medicine, University of Perugia, Ospedale S.M. della Misericordia, Edificio C, 5° piano, Piazzale Menghini 1, 06129 S. Andrea delle Fratte, Perugia, Italy
2
Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, University Hospital Center Zagreb and University of Zagreb School of Medicine, 10000 Zagreb, Croatia
3
Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine, “Attikon” University Hospital, 12462 Athens, Greece
4
Department of Rheumatology, “Asklepieion” General Hospital, 16673 Athens, Greece
5
Laboratory of Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
6
Joint Academic Rheumatology Program, Medical School, National and Kapodestrian University of Athens, Athens, Greece and Medical School, University of Cyprus, 1678 Nicosia, Cyprus
*
Author to whom correspondence should be addressed.
Cells 2019, 8(8), 898; https://doi.org/10.3390/cells8080898
Received: 26 July 2019 / Revised: 12 August 2019 / Accepted: 13 August 2019 / Published: 15 August 2019
(This article belongs to the Special Issue The Molecular and Cellular Basis for Lupus)
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. View Full-Text
Keywords: systemic lupus erythematosus; Janus kinase; protein tyrosine kinases; STAT; baricitinib systemic lupus erythematosus; Janus kinase; protein tyrosine kinases; STAT; baricitinib
MDPI and ACS Style

Alunno, A.; Padjen, I.; Fanouriakis, A.; Boumpas, D.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. Cells 2019, 8, 898.

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