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Pharmacological Reviews Apr 2020Before it was molecularly cloned in 1994, acute-phase response factor or signal transducer and activator of transcription (STAT)3 was the focus of intense research into... (Review)
Review
Before it was molecularly cloned in 1994, acute-phase response factor or signal transducer and activator of transcription (STAT)3 was the focus of intense research into understanding the mammalian response to injury, particularly the acute-phase response. Although known to be essential for liver production of acute-phase reactant proteins, many of which augment innate immune responses, molecular cloning of acute-phase response factor or STAT3 and the research this enabled helped establish the central function of Janus kinase (JAK) family members in cytokine signaling and identified a multitude of cytokines and peptide hormones, beyond interleukin-6 and its family members, that activate JAKs and STAT3, as well as numerous new programs that their activation drives. Many, like the acute-phase response, are adaptive, whereas several are maladaptive and lead to chronic inflammation and adverse consequences, such as cachexia, fibrosis, organ dysfunction, and cancer. Molecular cloning of STAT3 also enabled the identification of other noncanonical roles for STAT3 in normal physiology, including its contribution to the function of the electron transport chain and oxidative phosphorylation, its basal and stress-related adaptive functions in mitochondria, its function as a scaffold in inflammation-enhanced platelet activation, and its contributions to endothelial permeability and calcium efflux from endoplasmic reticulum. In this review, we will summarize the molecular and cellular biology of JAK/STAT3 signaling and its functions under basal and stress conditions, which are adaptive, and then review maladaptive JAK/STAT3 signaling in animals and humans that lead to disease, as well as recent attempts to modulate them to treat these diseases. In addition, we will discuss how consideration of the noncanonical and stress-related functions of STAT3 cannot be ignored in efforts to target the canonical functions of STAT3, if the goal is to develop drugs that are not only effective but safe. SIGNIFICANCE STATEMENT: Key biological functions of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling can be delineated into two broad categories: those essential for normal cell and organ development and those activated in response to stress that are adaptive. Persistent or dysregulated JAK/STAT3 signaling, however, is maladaptive and contributes to many diseases, including diseases characterized by chronic inflammation and fibrosis, and cancer. A comprehensive understanding of JAK/STAT3 signaling in normal development, and in adaptive and maladaptive responses to stress, is essential for the continued development of safe and effective therapies that target this signaling pathway.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Fibrosis; Humans; Inflammation; Janus Kinases; Molecular Targeted Therapy; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; STAT3 Transcription Factor
PubMed: 32198236
DOI: 10.1124/pr.119.018440 -
The New England Journal of Medicine Jun 2023Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and...
BACKGROUND
Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high.
METHODS
We evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy.
RESULTS
Genome sequencing revealed three novel heterozygous missense gain-of-function variants in . In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition.
CONCLUSIONS
Gain-of-function variants in caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).
Topics: Janus Kinases; Nitriles; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Autoimmune Diseases; Mutation, Missense; Gain of Function Mutation; Dermatologic Agents; Anti-Inflammatory Agents
PubMed: 37256972
DOI: 10.1056/NEJMoa2202318 -
Indian Journal of Dermatology,...Recent studies on molecular pathways have elucidated novel therapeutic approaches in inflammatory and autoimmune skin disorders. Specifically, the dysregulation of the... (Review)
Review
Janus-kinase inhibitors in dermatology: A review of their use in psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease.
Recent studies on molecular pathways have elucidated novel therapeutic approaches in inflammatory and autoimmune skin disorders. Specifically, the dysregulation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) cascade plays a central role in the pathogenesis of many skin conditions. JAK inhibitors, with their ability to selectively target immune responses, are potential treatment options. Using the National Library of Medicine, we provide a comprehensive review of the use of United States Food and Drug Administration (FDA)-approved and emerging JAK or tyrosine kinase 2 (TYK2) inhibitors in a wide range of dermatologic conditions, including psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. In patients with psoriasis, oral deucravacitinib (TYK2 inhibitor) has been approved as a once-daily therapy with demonstrated superiority and efficacy over apremilast and placebo and tolerable safety profiles. In patients with vitiligo, topical ruxolitinib (JAK1 inhibitor) is approved as a twice-daily treatment for repigmentation. The efficacy of several other JAK inhibitors has also been demonstrated in several clinical trials and case studies for systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. Further investigations with long-term clinical trials are necessary to confirm their utility in treatment and safety for these diseases.
Topics: Humans; Janus Kinase Inhibitors; Vitiligo; Dermatology; Dermatomyositis; Hidradenitis Suppurativa; Psoriasis; Lichen Planus; Janus Kinases; Lupus Erythematosus, Systemic; Sarcoidosis; Graft vs Host Disease
PubMed: 38031699
DOI: 10.25259/IJDVL_15_2023 -
Frontiers in Immunology 2019Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the... (Review)
Review
Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the bone marrow from hematopoietic stem cells (HSCs) that differentiate through common lymphoid progenitors (CLPs) to NK lineage-restricted progenitors (NKPs). The orchestrated action of multiple cytokines is crucial for NK cell development and maturation. Many of these cytokines such as IL-2, IL-7, IL-12, IL-15, IL-21, IL-27, and interferons (IFNs) signal via the Janus Kinase / Signal Transducer and Activator of Transcription (JAK/STAT) pathway. We here review the current knowledge about these cytokines and the downstream signaling involved in the development and maturation of conventional NK cells and their close relatives, innate lymphoid cells type 1 (ILC1). We further discuss the role of suppressor of cytokine signaling (SOCS) proteins in NK cells and highlight their potential for therapeutic application.
Topics: Biomarkers; Cell Differentiation; Cytokines; Gene Expression Regulation; Humans; Janus Kinases; Killer Cells, Natural; STAT Transcription Factors; Signal Transduction
PubMed: 31781102
DOI: 10.3389/fimmu.2019.02590 -
Annals of the Rheumatic Diseases Jan 2024Fundamental insight gained over the last decades led to the discovery of cytokines as pivotal drivers of inflammatory diseases such as rheumatoid arthritis,... (Review)
Review
Fundamental insight gained over the last decades led to the discovery of cytokines as pivotal drivers of inflammatory diseases such as rheumatoid arthritis, psoriasis/psoriasis arthritis, inflammatory bowel diseases, atopic dermatitis and spondylarthritis. A deeper understanding of the pro-inflammatory and anti-inflammatory effects of various cytokines has prompted new cytokine-targeting therapies, which revolutionised the treatment options in the last years for patients with inflammatory disorders. Disease-associated immune responses typically involve a complex interplay of multiple cytokines. Therefore, blockade of one single cytokine does not necessarily lead to a persistent remission in all patients with inflammatory disorders and fostered new therapeutic strategies targeting intracellular pathways shared by multiple cytokines. By inhibiting JAK-STAT signalling pathways common to families of cytokines, JAK-inhibitors (JAKinibs) have created a new paradigm for the treatment of inflammatory diseases. Multiple agents have been approved for various disorders and more are being investigated for several new indications. Second-generation selective JAKinibs have been devised with the aim to achieve an increased selectivity and a possible reduced risk of side effects. In the current review, we will summarise the current body of evidence of pan versus selective JAKinibs and the most recent insights on new side effects and indications, including COVID-19.
Topics: Humans; Janus Kinase Inhibitors; Autoimmune Diseases; Arthritis, Rheumatoid; Cytokines; Arthritis, Psoriatic; Janus Kinases
PubMed: 37923366
DOI: 10.1136/ard-2023-223850 -
The Journal of Allergy and Clinical... Jun 2022Psoriasis, a chronic inflammatory disease dependent on the IL-23/T17 pathway, is initiated through plasmacytoid dendritic cell activation and type I IFN induction in the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Psoriasis, a chronic inflammatory disease dependent on the IL-23/T17 pathway, is initiated through plasmacytoid dendritic cell activation and type I IFN induction in the skin. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, blocks IL-23, IL-12, and type I IFN signaling in cellular assays.
OBJECTIVE
We investigated changes in IL-23/T17 and type I IFN pathway biomarkers and gene responses as well as measures of selectivity for TYK2 over Janus kinases (JAKs) 1-3 in patients with moderate to severe psoriasis receiving deucravacitinib.
METHODS
Deucravacitinib was evaluated in a randomized, placebo-controlled, dose-ranging trial. Biopsy samples from nonlesional (day 1) and lesional skin (days 1, 15, and 85) were assessed for changes in IL-23/IL-12 and type I IFN pathway biomarkers by quantitative reverse-transcription polymerase chain reaction, RNA sequencing, and immunohistochemistry. Laboratory markers were measured in blood. Percentage change from baseline in Psoriasis Area and Severity Index (PASI) score was assessed.
RESULTS
IL-23 pathway biomarkers in lesional skin returned toward nonlesional levels dose-dependently with deucravacitinib. IFN and IL-12 pathway genes were normalized. Markers of keratinocyte dysregulation, keratin-16, and β-defensin genes approached nonlesional levels with effective doses. Select laboratory parameters affected by JAK1-3 inhibition were not affected by deucravacitinib. Greater improvements in PASI scores, correlated with biomarker changes, were seen with the highest doses of deucravacitinib versus lower doses or placebo.
CONCLUSION
Robust clinical efficacy with deucravacitinib treatment was associated with decreases in IL-23/T17 and IFN pathway biomarkers. The lack of effect seen on biomarkers specific to JAK1-3 inhibition supports selectivity of deucravacitinib for TYK2; larger confirmatory studies are needed.
Topics: Biomarkers; Heterocyclic Compounds; Humans; Interferon Type I; Interleukin-12; Interleukin-23; Psoriasis; TYK2 Kinase
PubMed: 34767869
DOI: 10.1016/j.jaci.2021.11.001 -
Science (New York, N.Y.) Apr 2022Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron...
Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure of full-length JAK1 complexed with a cytokine receptor intracellular domain Box1 and Box2 regions captured as an activated homodimer bearing the valine→phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains of JAK1 form an extended structural unit, the dimerization of which is mediated by close-packing of the pseudokinase (PK) domains from the monomeric subunits. The oncogenic VF mutation lies within the core of the JAK1 PK interdimer interface, enhancing packing complementarity to facilitate ligand-independent activation. The carboxy-terminal tyrosine kinase domains are poised for transactivation and to phosphorylate the receptor STAT (signal transducer and activator of transcription)-recruiting motifs projecting from the overhanging FERM (four-point-one, ezrin, radixin, moesin)-SH2 (Src homology 2)-domains. Mapping of constitutively active JAK mutants supports a two-step allosteric activation mechanism and reveals opportunities for selective therapeutic targeting of oncogenic JAK signaling.
Topics: Allosteric Regulation; Cryoelectron Microscopy; Enzyme Activation; Humans; Janus Kinase 1; Mutation; Myeloproliferative Disorders; Phosphorylation; Protein Multimerization; Receptors, Cytokine; STAT Transcription Factors; src Homology Domains
PubMed: 35271300
DOI: 10.1126/science.abn8933 -
Acta Dermato-venereologica Feb 2023Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is... (Review)
Review
Itch is a common skin symptom, with complex aetiology and pathogenesis. It is mediated by 2 pathways, the histaminergic and non-histaminergic pathways. Chronic itch is understood to be processed by the latter and is difficult to treat with traditional pruritus therapies. The Janus kinase and signal transducer and activator of transcription pathway is a signalling mechanism that regulates gene expression through various cytokines. Janus kinase inhibitors, which have been tested and used for several autoimmune diseases, have also been shown to be effective for itch through clinical trials and case reports. Janus kinase inhibitors could be a good choice for pruritus in atopic dermatitis, psoriasis, and other diseases, such as prurigo nodularis and lichen planus, with rapid itch relief compared with conventional treatments. The most common adverse effects reported include nasopharyngitis, acne, and elevated blood creatine phosphokinase levels. Janus kinase inhibitors are currently prescribed with warnings about a potential increase in malignancies and cardiovascular diseases and usage in people of older ages. This review aims to provide knowledge about itch and the Janus kinase and signal transducer and activator of transcription pathway and to analyse the current evidence for itch relief by Janus kinase inhibitors.
Topics: Humans; Dermatitis, Atopic; Janus Kinase Inhibitors; Janus Kinases; Pruritus; Skin Diseases
PubMed: 36789757
DOI: 10.2340/actadv.v103.5346 -
Clinical and Translational Science Jan 2024Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other... (Review)
Review
Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other agencies around the world for the treatment of several chronic inflammatory diseases, including rheumatic, dermatologic, and gastrointestinal diseases. Through inhibition of JAK, upadacitinib inhibits phosphorylation of downstream effector proteins, which consequently inhibits cytokine signaling for key pathways involved in inflammatory diseases. Upadacitinib more potently inhibits JAK1 than other JAK isoforms. The pharmacokinetics, pharmacodynamics, efficacy, and safety of upadacitinib were characterized in many clinical trials, which demonstrated the superiority of upadacitinib treatment over placebo or an active comparator in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis. The safety profile of upadacitinib supported a favorable benefit-risk profile across all the approved indications. In this article, we review the mechanism of action of upadacitinib and describe how the JAK-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in the pathogenesis of several chronic and progressive immune-mediated inflammatory diseases. In addition, this review also provides an overview of key clinical trials that were conducted as well as relevant data which supported the clinical development of upadacitinib and informed the recommended dose(s) in each of the approved indications.
Topics: United States; Humans; Translational Science, Biomedical; Arthritis, Rheumatoid; Spondylitis, Ankylosing; Janus Kinase Inhibitors; Janus Kinases; Heterocyclic Compounds, 3-Ring
PubMed: 37984057
DOI: 10.1111/cts.13688 -
Cell Reports Mar 2023Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK...
Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans-phosphorylation, and activation. Activated JAKs in turn phosphorylate receptor intracellular domains (ICDs), resulting in the recruitment, phosphorylation, and activation of signal transducer and activator of transcription (STAT)-family transcription factors. The structural arrangement of a JAK1 dimer complex with IFNλR1 ICD was recently elucidated while bound by stabilizing nanobodies. While this revealed insights into the dimerization-dependent activation of JAKs and the role of oncogenic mutations in this process, the tyrosine kinase (TK) domains were separated by a distance not compatible with the trans-phosphorylation events between the TK domains. Here, we report the cryoelectron microscopy structure of a mouse JAK1 complex in a putative trans-activation state and expand these insights to other physiologically relevant JAK complexes, providing mechanistic insight into the crucial trans-activation step of JAK signaling and allosteric mechanisms of JAK inhibition.
Topics: Animals; Mice; Janus Kinases; DNA-Binding Proteins; Cryoelectron Microscopy; Trans-Activators; Janus Kinase 1; Signal Transduction; Phosphorylation; Janus Kinase 2; Janus Kinase 3
PubMed: 36867534
DOI: 10.1016/j.celrep.2023.112201