Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
6.1
4.3
Journals
Pharmaceuticals
Special Issues
The Regulation of JAKs in Health and in Disease
share announcement

The Regulation of JAKs in Health and in Disease

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 69735

Special Issue Editors

Dr. Bobin George Abraham

E-Mail
Guest Editor
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Interests: receptors; JAKs; cell imaging; signaling; cancer; immunology
Dr. Anniina T. Virtanen

E-Mail
Guest Editor
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Interests: cytokine signaling; immunology; cancer; immune diseases; jak inhibitors

Special Issue Information

Dear Colleagues,

JAK kinases mediate signaling from approximately 60 cytokines and hormones in the regulation of hematopoiesis, metabolism, inflammation, and immune response. The activation of JAKs functions as the triggering signal for all cytokine signaling where STAT transcription factors are the prototypical substrates and the crosstalk between different signaling pathways underlie the appropriate cellular regulation and biological responses. Regulation of JAK kinase activity occurs at several levels and deregulated JAK signaling is involved in a multitude of human diseases especially in hematological and immunological diseases. The clinical relevance and questions have raised the need for detailed structural and mechanistic knowledge of JAK regulation both for understanding the pathogenesis of diseases as well as for therapeutic development. Recent years have seen increasing evidence on the potential of JAK inhibitors in modulating inflammatory and immune responses in human diseases. Currently, six JAKinibs are approved for the treatment of autoimmune diseases and myeloproliferative neoplasms and a dozen more are in clinical trials for various hematological, inflammatory, and immune diseases.

This Special Issue of Pharmaceuticals will focus on the most recent advances in the regulation of JAKs in cytokine signaling and in diseases and emerging therapeutic approaches. We invite original research articles, short communications, and reviews from basic science to case studies and clinical trials on topics including but not limited to the following:

  • Regulation of JAKs
  • JAK-STAT signaling
  • JAKs in hematological, inflammatory, and autoimmune diseases
  • Identification and characterization of pathogenic JAK mutations
  • JAK inhibitors: Methodology for assessment of biochemical features, efficacy or safety, development of novel inhibitors, pre-clinical studies, and clinical findings.

Dr. Bobin George Abraham
Dr. Anniina T. Virtanen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Janus kinase
  • JAK-STAT
  • Cytokine
  • JAK inhibitor
  • Autoimmune disease
  • Myeloproliferative neoplasms

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (13 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review, Other

17 pages, 2339 KiB  
Article
Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain
by Anniina T. Virtanen, Teemu Haikarainen, Parthasarathy Sampathkumar, Maaria Palmroth, Sanna Liukkonen, Jianping Liu, Natalia Nekhotiaeva, Stevan R. Hubbard and Olli Silvennoinen
Pharmaceuticals 2023, 16(1), 75; https://doi.org/10.3390/ph16010075 - 4 Jan 2023
Cited by 8 | Viewed by 7743
Abstract
Hyperactive mutation V617F in the JAK2 regulatory pseudokinase domain (JH2) is prevalent in patients with myeloproliferative neoplasms. Here, we identified novel small molecules that target JH2 of JAK2 V617F and characterized binding via biochemical and structural approaches. Screening of 107,600 small molecules resulted [...] Read more.
Hyperactive mutation V617F in the JAK2 regulatory pseudokinase domain (JH2) is prevalent in patients with myeloproliferative neoplasms. Here, we identified novel small molecules that target JH2 of JAK2 V617F and characterized binding via biochemical and structural approaches. Screening of 107,600 small molecules resulted in identification of 55 binders to the ATP-binding pocket of recombinant JAK2 JH2 V617F protein at a low hit rate of 0.05%, which indicates unique structural characteristics of the JAK2 JH2 ATP-binding pocket. Selected hits and structural analogs were further assessed for binding to JH2 and JH1 (kinase) domains of JAK family members (JAK1-3, TYK2) and for effects on MPN model cell viability. Crystal structures were determined with JAK2 JH2 wild-type and V617F. The JH2-selective binders were identified in diaminotriazole, diaminotriazine, and phenylpyrazolo-pyrimidone chemical entities, but they showed low-affinity, and no inhibition of MPN cells was detected, while compounds binding to both JAK2 JH1 and JH2 domains inhibited MPN cell viability. X-ray crystal structures of protein-ligand complexes indicated generally similar binding modes between the ligands and V617F or wild-type JAK2. Ligands of JAK2 JH2 V617F are applicable as probes in JAK-STAT research, and SAR optimization combined with structural insights may yield higher-affinity inhibitors with biological activity. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

21 pages, 4048 KiB  
Article
Impact of MnTBAP and Baricitinib Treatment on Hutchinson–Gilford Progeria Fibroblasts
by Elena Vehns, Rouven Arnold and Karima Djabali
Pharmaceuticals 2022, 15(8), 945; https://doi.org/10.3390/ph15080945 - 29 Jul 2022
Cited by 2 | Viewed by 2422
Abstract
Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging disease. It is caused by a mutation in the LMNA gene, which results in a 50-amino-acid truncation of prelamin A. The resultant truncated prelamin A (progerin) lacks the cleavage site for the zinc-metallopeptidase ZMPSTE24. [...] Read more.
Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging disease. It is caused by a mutation in the LMNA gene, which results in a 50-amino-acid truncation of prelamin A. The resultant truncated prelamin A (progerin) lacks the cleavage site for the zinc-metallopeptidase ZMPSTE24. Progerin is permanently farnesylated, carboxymethylated, and strongly anchored to the nuclear envelope. This leads to abnormalities, such as altered nuclear shape, mitochondrial dysfunction, and inflammation. HGPS patients display symptoms of physiological aging, including atherosclerosis, alopecia, lipodystrophy, and arthritis. Currently, no cure for HGPS exists. Here we focus on a drug combination consisting of the superoxide dismutase mimetic MnTBAP and JAK1/2 inhibitor baricitinib (Bar) to restore phenotypic alterations in HGPS fibroblasts. Treating HGPS fibroblasts with the MnTBAP/Bar combination improved mitochondrial functions and sustained Bar’s positive effects on reducing progerin and pro-inflammatory factor levels. Collectively, MnTBAP/Bar combination treatment ameliorates the aberrant phenotype of HGPS fibroblasts and is a potential treatment strategy for patients with HGPS. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

14 pages, 5603 KiB  
Article
Tyrphostin AG1024 Suppresses Coronaviral Replication by Downregulating JAK1 via an IR/IGF-1R Independent Proteolysis Mediated by Ndfip1/2_NEDD4-like E3 Ligase Itch
by Cheng-Wei Yang, Yue-Zhi Lee, Hsing-Yu Hsu, Guan-Hao Zhao and Shiow-Ju Lee
Pharmaceuticals 2022, 15(2), 241; https://doi.org/10.3390/ph15020241 - 17 Feb 2022
Cited by 3 | Viewed by 2582
Abstract
JAK1 depletion or downregulation was previously reported to account for coronavirus inhibition. Here, we found that AG1024, an IR (insulin receptor) and IGF-1R (insulin-like growth factor 1 receptor) inhibitor, diminishes JAK1 protein levels and exerts anti-coronaviral activities with EC50 values of 5.2 [...] Read more.
JAK1 depletion or downregulation was previously reported to account for coronavirus inhibition. Here, we found that AG1024, an IR (insulin receptor) and IGF-1R (insulin-like growth factor 1 receptor) inhibitor, diminishes JAK1 protein levels and exerts anti-coronaviral activities with EC50 values of 5.2 ± 0.3 μM against transmissible gastroenteritis coronavirus (TGEV) and 4.3 ± 0.3 μM against human flu coronavirus OC43. However, although the IR and IGF-1R signaling pathways are activated by insulin or IGF-1 in swine testis cells, they are not triggered upon TGEV infection. AG1024, therefore, inhibits coronaviral replication and downregulates JAK1 protein levels independently of IR and IGF-1R. Moreover, JAK1 proteolysis caused by AG1024 was found through activation of upstream Ndfip1/2 and its effector NEDD4-like E3 ligase Itch. In addition, ouabain, which was reported to mediate JAK1 proteolysis causing anti-coronaviral activity by activation of Ndfip1/2 and NEDD4 E3 ligase, additively inhibited anti-coronaviral activity and JAK1 diminishment in combination with AG1024. This study provides novel insights into the pharmacological effects of AG1024 and Itch E3 ligase mediated JAK1 proteolysis and identified Ndfip1/2 as a cognate effector for JAK1 proteolysis via the diversified E3 ligases NEDD4 and NEDD4-like Itch. These findings are expected to provide valued information for the future development of anti-viral agents. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Graphical abstract

12 pages, 2395 KiB  
Article
Molecular Modeling Insights into Upadacitinib Selectivity upon Binding to JAK Protein Family
by Amir Taldaev, Vladimir R. Rudnev, Kirill S. Nikolsky, Liudmila I. Kulikova and Anna L. Kaysheva
Pharmaceuticals 2022, 15(1), 30; https://doi.org/10.3390/ph15010030 - 25 Dec 2021
Cited by 12 | Viewed by 3972
Abstract
Rheumatoid arthritis (RA) is a chronic disease characterized by bone joint damage and incapacitation. The mechanism underlying RA pathogenesis is autoimmunity in the connective tissue. Cytokines play an important role in the human immune system for signal transduction and in the development of [...] Read more.
Rheumatoid arthritis (RA) is a chronic disease characterized by bone joint damage and incapacitation. The mechanism underlying RA pathogenesis is autoimmunity in the connective tissue. Cytokines play an important role in the human immune system for signal transduction and in the development of inflammatory responses. Janus kinases (JAK) participate in the JAK/STAT pathway, which mediates cytokine effects, in particular interleukin 6 and IFNγ. The discovery of small molecule inhibitors of the JAK protein family has led to a revolution in RA therapy. The novel JAK inhibitor upadacitinib (RinvoqTM) has a higher selectivity for JAK1 compared to JAK2 and JAK3 in vivo. Currently, details on the molecular recognition of JAK1 by upadacitinib are not available. We found that characteristics of hydrogen bond formation with the glycine loop and hinge in JAKs define the selectivity. Our molecular modeling study could provide insight into the drug action mechanism and pharmacophore model differences in JAK isoforms. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

13 pages, 3076 KiB  
Article
Inhalation of Essential Oil from Mentha piperita Ameliorates PM10-Exposed Asthma by Targeting IL-6/JAK2/STAT3 Pathway Based on a Network Pharmacological Analysis
by Mi Hye Kim, Sang Jun Park and Woong Mo Yang
Pharmaceuticals 2021, 14(1), 2; https://doi.org/10.3390/ph14010002 - 22 Dec 2020
Cited by 13 | Viewed by 5501
Abstract
Fine particulate matter (PM) exposure exhibits a crucial risk factor to exacerbate airway epithelial remodeling, fibrosis, and pulmonary destruction in asthma. Based on the use of essential oils from aromatic plants on pain relief and anti-inflammatory properties, we investigated the inhibitory effects of [...] Read more.
Fine particulate matter (PM) exposure exhibits a crucial risk factor to exacerbate airway epithelial remodeling, fibrosis, and pulmonary destruction in asthma. Based on the use of essential oils from aromatic plants on pain relief and anti-inflammatory properties, we investigated the inhibitory effects of essential oil derived from the Mentha species (MEO) against asthma exposed to PM10. The MEO (0.1 v/v %) was aerosolized by a nebulizer to ovalbumin and PM10-induced asthmatic mice. Histological changes were confirmed in the lung tissues. To define the mode of action of the MEO on asthma, a protein–protein interaction network was constructed using menthol and menthone as the major components of the MEO. Cytokine expression and the JAK2/STAT3 signaling pathway were analyzed in lung epithelial A549 cells co-treated with MEO and PM10. Inhalation of MEO by nebulization inhibited respiratory epithelium hyperplasia, collagen deposition, and goblet cell activation in asthmatic mice. Through a network pharmacological analysis, cytokine–cytokine receptor interaction and JAK/STAT was expected to be underlying mechanisms of MEO on asthma. Treatment with MEO significantly reduced the IL-6 levels with a decrease in pro-inflammatory and T helper 2-specific cytokines. PM10-induced phosphorylation of JAK2 and STAT3 was significantly decreased by MEO. Collectively, MEO may have an inhibitory effect on asthma under the condition of PM10 exposure through the IL-6/JAK2/STAT3 signaling pathway. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Graphical abstract

Review

Jump to: Research, Other

18 pages, 1481 KiB  
Review
Jak Inhibitors for Treatment of Autoimmune Diseases: Lessons from Systemic Sclerosis and Systemic Lupus Erythematosus
by Przemysław Kotyla, Olga Gumkowska-Sroka, Bartosz Wnuk and Kacper Kotyla
Pharmaceuticals 2022, 15(8), 936; https://doi.org/10.3390/ph15080936 - 28 Jul 2022
Cited by 13 | Viewed by 3440
Abstract
Systemic sclerosis and systemic lupus erythematosus represent two distinct autoimmune diseases belonging to the group of connective tissue disorders. Despite the great progress in the basic science, this progress has not been translated to the development of novel therapeutic approaches that can radically [...] Read more.
Systemic sclerosis and systemic lupus erythematosus represent two distinct autoimmune diseases belonging to the group of connective tissue disorders. Despite the great progress in the basic science, this progress has not been translated to the development of novel therapeutic approaches that can radically change the face of these diseases. The discovery of JAK kinases, which are tyrosine kinases coupled with cytokine receptors, may open a new chapter in the treatment of so far untreatable diseases. Small synthetic compounds that can block Janus kinases and interact directly with cytokine signalling may provide therapeutic potential in these diseases. In this review, we discuss the therapeutic potential of Jak kinases in light of the cytokine network that JAK kinases are able to interact with. We also provide the theoretical background for the rationale of blocking cytokines with specific JAK inhibitors. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

13 pages, 1372 KiB  
Review
JAK2 in Myeloproliferative Neoplasms: Still a Protagonist
by Michael Stephan Bader and Sara Christina Meyer
Pharmaceuticals 2022, 15(2), 160; https://doi.org/10.3390/ph15020160 - 28 Jan 2022
Cited by 19 | Viewed by 4872
Abstract
The discovery of the activating V617F mutation in Janus kinase 2 (JAK2) has been decisive for the understanding of myeloproliferative neoplasms (MPN). Activated JAK2 signaling by JAK2, CALR, and MPL mutations has become a focus for the development of targeted therapies for [...] Read more.
The discovery of the activating V617F mutation in Janus kinase 2 (JAK2) has been decisive for the understanding of myeloproliferative neoplasms (MPN). Activated JAK2 signaling by JAK2, CALR, and MPL mutations has become a focus for the development of targeted therapies for patients with MPN. JAK2 inhibitors now represent a standard of clinical care for certain forms of MPN and offer important benefits for MPN patients. However, several key aspects remain unsolved regarding the targeted therapy of MPN with JAK2 inhibitors, such as reducing the MPN clone and how to avoid or overcome a loss of response. Here, we summarize the current knowledge on the structure and signaling of JAK2 as central elements of MPN pathogenesis and feature benefits and limitations of therapeutic JAK2 targeting in MPN. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

32 pages, 886 KiB  
Review
Jakinibs of All Trades: Inhibiting Cytokine Signaling in Immune-Mediated Pathologies
by Madison Alexander, Yiming Luo, Giorgio Raimondi, John J. O’Shea and Massimo Gadina
Pharmaceuticals 2022, 15(1), 48; https://doi.org/10.3390/ph15010048 - 30 Dec 2021
Cited by 23 | Viewed by 8576
Abstract
Over the last 25 years, inhibition of Janus kinases (JAKs) has been pursued as a modality for treating various immune and inflammatory disorders. While the clinical development of JAK inhibitors (jakinibs) began with the investigation of their use in allogeneic transplantation, their widest [...] Read more.
Over the last 25 years, inhibition of Janus kinases (JAKs) has been pursued as a modality for treating various immune and inflammatory disorders. While the clinical development of JAK inhibitors (jakinibs) began with the investigation of their use in allogeneic transplantation, their widest successful application came in autoimmune and allergic diseases. Multiple molecules have now been approved for diseases ranging from rheumatoid and juvenile arthritis to ulcerative colitis, atopic dermatitis, graft-versus-host-disease (GVHD) and other inflammatory pathologies in 80 countries around the world. Moreover, two jakinibs have also shown surprising efficacy in the treatment of hospitalized coronavirus disease-19 (COVID-19) patients, indicating additional roles for jakinibs in infectious diseases, cytokine storms and other hyperinflammatory syndromes. Jakinibs, as a class of pharmaceutics, continue to expand in clinical applications and with the development of more selective JAK-targeting and organ-selective delivery. Importantly, jakinib safety and pharmacokinetics have been investigated alongside clinical development, further cementing the potential benefits and limits of jakinib use. This review covers jakinibs that are approved or are under late phase investigation, focusing on clinical applications, pharmacokinetic and safety profiles, and future opportunities and challenges. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Graphical abstract

10 pages, 1511 KiB  
Review
The Role of LNK (SH2B3) in the Regulation of JAK-STAT Signalling in Haematopoiesis
by Rhiannon Morris, Liesl Butler, Andrew Perkins, Nadia J. Kershaw and Jeffrey J. Babon
Pharmaceuticals 2022, 15(1), 24; https://doi.org/10.3390/ph15010024 - 24 Dec 2021
Cited by 16 | Viewed by 5360
Abstract
LNK is a member of the SH2B family of adaptor proteins and is a non-redundant regulator of cytokine signalling. Cytokines are secreted intercellular messengers that bind to specific receptors on the surface of target cells to activate the Janus Kinase-Signal Transducer and Activator [...] Read more.
LNK is a member of the SH2B family of adaptor proteins and is a non-redundant regulator of cytokine signalling. Cytokines are secreted intercellular messengers that bind to specific receptors on the surface of target cells to activate the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling pathway. Activation of the JAK-STAT pathway leads to proliferative and often inflammatory effects, and so the amplitude and duration of signalling are tightly controlled. LNK binds phosphotyrosine residues to signalling proteins downstream of cytokines and constrains JAK-STAT signalling. Mutations in LNK have been identified in a range of haematological and inflammatory diseases due to increased signalling following the loss of LNK function. Here, we review the regulation of JAK-STAT signalling via the adaptor protein LNK and discuss the role of LNK in haematological diseases. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

14 pages, 1875 KiB  
Review
JAK-STAT Pathway Regulation of Intestinal Permeability: Pathogenic Roles and Therapeutic Opportunities in Inflammatory Bowel Disease
by Hillmin Lei, Meli’sa S. Crawford and Declan F. McCole
Pharmaceuticals 2021, 14(9), 840; https://doi.org/10.3390/ph14090840 - 25 Aug 2021
Cited by 21 | Viewed by 5287
Abstract
The epithelial barrier forms the interface between luminal microbes and the host immune system and is the first site of exposure to many of the environmental factors that trigger disease activity in chronic inflammatory bowel disease (IBD). Disruption of the epithelial barrier, in [...] Read more.
The epithelial barrier forms the interface between luminal microbes and the host immune system and is the first site of exposure to many of the environmental factors that trigger disease activity in chronic inflammatory bowel disease (IBD). Disruption of the epithelial barrier, in the form of increased intestinal permeability, is a feature of IBD and other inflammatory diseases, including celiac disease and type 1 diabetes. Variants in genes that regulate or belong to the JAK-STAT signaling pathway are associated with IBD risk. Inhibitors of the JAK-STAT pathway are now effective therapeutic options in IBD. This review will discuss emerging evidence that JAK inhibitors can be used to improve defects in intestinal permeability and how this plays a key role in resolving intestinal inflammation. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

22 pages, 936 KiB  
Review
Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues
by Milo Gatti, Eleonora Turrini, Emanuel Raschi, Piero Sestili and Carmela Fimognari
Pharmaceuticals 2021, 14(8), 738; https://doi.org/10.3390/ph14080738 - 28 Jul 2021
Cited by 33 | Viewed by 6782
Abstract
We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as [...] Read more.
We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

18 pages, 1134 KiB  
Review
Deregulation of the Interleukin-7 Signaling Pathway in Lymphoid Malignancies
by Inge Lodewijckx and Jan Cools
Pharmaceuticals 2021, 14(5), 443; https://doi.org/10.3390/ph14050443 - 8 May 2021
Cited by 15 | Viewed by 5584
Abstract
The cytokine interleukin-7 (IL-7) and its receptor are critical for lymphoid cell development. The loss of IL-7 signaling causes severe combined immunodeficiency, whereas gain-of-function alterations in the pathway contribute to malignant transformation of lymphocytes. Binding of IL-7 to the IL-7 receptor results in [...] Read more.
The cytokine interleukin-7 (IL-7) and its receptor are critical for lymphoid cell development. The loss of IL-7 signaling causes severe combined immunodeficiency, whereas gain-of-function alterations in the pathway contribute to malignant transformation of lymphocytes. Binding of IL-7 to the IL-7 receptor results in the activation of the JAK-STAT, PI3K-AKT and Ras-MAPK pathways, each contributing to survival, cell cycle progression, proliferation and differentiation. Here, we discuss the role of deregulated IL-7 signaling in lymphoid malignancies of B- and T-cell origin. Especially in T-cell leukemia, more specifically in T-cell acute lymphoblastic leukemia and T-cell prolymphocytic leukemia, a high frequency of mutations in components of the IL-7 signaling pathway are found, including alterations in IL7R, IL2RG, JAK1, JAK3, STAT5B, PTPN2, PTPRC and DNM2 genes. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

Other

Jump to: Research, Review

14 pages, 1757 KiB  
Case Report
IRF2BP2 Mutation Is Associated with Increased STAT1 and STAT5 Activation in Two Family Members with Inflammatory Conditions and Lymphopenia
by Maaria Palmroth, Hanna Viskari, Mikko R. J. Seppänen, Salla Keskitalo, Anniina Virtanen, Markku Varjosalo, Olli Silvennoinen and Pia Isomäki
Pharmaceuticals 2021, 14(8), 797; https://doi.org/10.3390/ph14080797 - 13 Aug 2021
Cited by 8 | Viewed by 5311
Abstract
Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional coregulator that has an important role in the regulation of the immune response. IRF2BP2 has been associated with the Janus kinase (JAK)—signal transducers and activators of transcription (STAT) pathway, but its exact [...] Read more.
Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional coregulator that has an important role in the regulation of the immune response. IRF2BP2 has been associated with the Janus kinase (JAK)—signal transducers and activators of transcription (STAT) pathway, but its exact role remains elusive. Here, we identified a novel clinical variant, IRF2BP2 c.625_665del, from two members of a family with inflammatory conditions and investigated the function of IRF2BP2 and c.625_665del mutation in JAK–STAT pathway activation and inflammatory signaling. The levels of constitutive and cytokine-induced phosphorylation of STATs and total STAT1 in peripheral blood monocytes, T cells, and B cells from the patients and four healthy controls were measured by flow cytometry. Inflammation-related gene expression was studied in peripheral blood mononuclear cells using direct digital detection of mRNA (NanoString). Finally, we studied the relationship between IRF2BP2 and STAT1 activation using a luciferase reporter system in a cell model. Our results show that patients having the IRF2BP2 c.625_665del mutation presented overexpression of STAT1 protein and increased constitutive activation of STAT1. In addition, interferon-induced JAK–STAT signaling was upregulated, and several interferon-inducible genes were overexpressed. Constitutive phosphorylation of STAT5 was also found to be upregulated in CD4+ T cells from the patients. Using a cell model, we show that IRF2BP2 was needed to attenuate STAT1 transcriptional activity and that IRF2BP2 c.625_665del mutation failed in this. We conclude that IRF2BP2 has an important role in suppressing immune responses elicited by STAT1 and STAT5 and suggest that aberrations in IRF2BP2 can lead to abnormal function of intrinsic immunity. Full article
(This article belongs to the Special Issue The Regulation of JAKs in Health and in Disease)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-13
Back to TopTop