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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Journal ArticleDOI
Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib.
Cui-Cui Liu,Zhuxi Huang,Xiao Li,Kai-Feng Shen,Meng Liu,Handong Ouyang,Su-Bo Zhang,Yu-Ting Ruan,Xiao-Long Zhang,Shaoling Wu,Wen-Jun Xin,Chao Ma +11 more
TL;DR: The results suggest that the upregulation of NLRP3 in DRG via STAT3‐dependent histone acetylation is critically involved in bortezomib‐induced mechanical allodynia.
Journal ArticleDOI
TGF-β–induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis
Clara Dees,Sebastian Pötter,Yun Zhang,Christina Bergmann,Xiang Zhou,Markus Luber,Thomas Wohlfahrt,Emmanuel Karouzakis,Andreas Ramming,Kolja Gelse,Akihiko Yoshimura,Rudolf Jaenisch,Oliver Distler,Georg Schett,Jörg H W Distler +14 more
TL;DR: Re-establishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGFβ-dependent fibroblast activation and ameliorated experimental fibrosis in murine models.
Journal ArticleDOI
JAK/STAT inhibitors and other small molecule cytokine antagonists for the treatment of allergic disease.
TL;DR: Emerging therapies currently in development may provide more consistent benefit to patients with allergic diseases by specifically targeting inflammatory pathways important for disease pathogenesis.
Journal ArticleDOI
The emerging role of Janus kinase inhibitors in the treatment of autoimmune and inflammatory diseases.
William Damsky,Danielle Peterson,Julie Y. Ramseier,Badr Al-Bawardy,Hyung J. Chun,Deborah D. Proctor,Vibeke Strand,Richard A. Flavell,Brett A. King +8 more
TL;DR: The biology of the JAK-STAT pathway and the use of JAK inhibitors to treat autoimmunity across medical subspecialties are reviewed.
Journal ArticleDOI
Sepsis Induces a Long-Lasting State of Trained Immunity in Bone Marrow Monocytes.
Katharina Bomans,Judith Schenz,Isabella Sztwiertnia,Dominik Schaack,Markus A. Weigand,Florian Uhle +5 more
TL;DR: It is demonstrated that sepsis via functional reprogramming of naïve bone marrow monocytes induces a cellular state of trained immunity, which might be counteracted depending on the compartmental localization of the cell.
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.