Journal ArticleDOI
Mechanisms and consequences of Jak–STAT signaling in the immune system
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TLDR
Recent advances in Jak–STAT biology are reviewed, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.Abstract:
Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.read more
Citations
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Role of IL-6 inhibitor in treatment of COVID-19-related cytokine release syndrome.
TL;DR: In this paper, the authors described the evidence of the IL-6 response in patients with severe coronavirus disease 2019, clarified the pathogenesis of the role of IL6-mediated CRS in severe COVID-19, and highlighted the rationale for the use of anti-IL-6 agents and key information regarding the potential features of these IL6 inhibitors in COVID19 patients.
Journal ArticleDOI
IL-23 and IL-2 activation of STAT5 is required for optimal IL-22 production in ILC3s during colitis.
David Bauché,Barbara Joyce-Shaikh,Julie Fong,Alejandro V. Villarino,Karin S. Ku,Renu Jain,Yu-chi Lee,Lakshmanan Annamalai,Jennifer H. Yearley,Daniel J. Cua +9 more
TL;DR: The precise roles of STAT5 signaling in group 3 innate lymphoid cells (ILC3s), a key subset of immune cells involved in the maintenance of gut barrier integrity, are elucidated and suggest that STAT5a/b signaling in ILC3s maintains gut epithelial integrity during pathogen-induced intestinal disease.
Journal ArticleDOI
Activation of naïve CD4 + T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4 + T cells.
Jason Peter Twohig,Ana Cardus Figueras,Robert Andrews,Florian Wiede,Benjamin C. Cossins,Alicia Derrac Soria,Myles Lewis,Michael J. Townsend,David Millrine,Jasmine Li,David Hill,Javier Uceda Fernandez,Xiao Liu,Barbara Szomolay,Chris Pepper,Chris Pepper,Philip R. Taylor,Costantino Pitzalis,Tony Tiganis,Nigel Williams,Gareth W. Jones,Gareth W. Jones,Simon Arnett Jones +22 more
TL;DR: Results show that activation of CD4+ T cells leads to suppression of STAT1 activation by tyrosine phosphatases and changes the effector characteristics of memory CD4- T cells in response to IL-6.
Journal ArticleDOI
Working and safety profiles of JAK/STAT signaling inhibitors. Are these small molecules also smart?
Elvira Favoino,Marcella Prete,Giacomo Catacchio,Piero Ruscitti,Luca Navarini,Roberto Giacomelli,Federico Perosa +6 more
TL;DR: In this article, the authors describe the physiology of intracellular JAK/STAT pathway signaling and the pathological conditions associated to its dysregulation, along with clinical data from registration studies showing the efficacy of these drugs.
Journal ArticleDOI
Feed-forward regulation between cellular senescence and immunosuppression promotes the aging process and age-related diseases
TL;DR: The immunosuppressive mechanisms which impair the surveillance and clearance of pro-inflammatory senescent cells with aging are examined and several therapeutic strategies to halt the degenerative feed-forward circuit associated with the aging process and age-related diseases are discussed.
References
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Journal ArticleDOI
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
TL;DR: The authors showed that CD4+CD25+ cells contribute to maintaining self-tolerance by downregulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage.
Journal ArticleDOI
Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins
TL;DR: A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
Journal ArticleDOI
A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
Robert Kralovics,Francesco Passamonti,Andreas Buser,Soon Siong Teo,Ralph Tiedt,Jakob Passweg,André Tichelli,Mario Cazzola,Radek C. Skoda +8 more
TL;DR: Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages and a high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.
Journal ArticleDOI
Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.
E. Joanna Baxter,Linda M. Scott,Peter J. Campbell,Clare L. East,Nasios Fourouclas,Soheila Swanton,George S. Vassiliou,Anthony J. Bench,Elaine M. Boyd,Natasha Curtin,Michael A. Scott,Wendy N. Erber,Anthony R. Green,Anthony R. Green +13 more
TL;DR: A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder and its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders.
Journal ArticleDOI
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera
Chloé James,Valérie Ugo,Jean-Pierre Le Couedic,Judith Staerk,François Delhommeau,Catherine Lacout,Loïc Garçon,Hana Raslova,Roland Berger,Annelise Bennaceur-Griscelli,Jean-Luc Villeval,Stefan N. Constantinescu,Nicole Casadevall,William Vainchenker +13 more
TL;DR: A clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.