scholarly journals Selective Janus kinase inhibition preserves interferon-λ–mediated antiviral responses

2021 ◽  
Vol 6 (59) ◽  
pp. eabd5318
Author(s):  
Daniel Schnepf ◽  
Stefania Crotta ◽  
Thiprampai Thamamongood ◽  
Megan Stanifer ◽  
Laura Polcik ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Influenza Virus Infection ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Type I ◽  
Antiviral Responses ◽  
Tyrosine Kinase 2 ◽  
Efficient Type ◽  
Janus Kinase Inhibition

Inflammatory diseases are frequently treated with Janus kinase (JAK) inhibitors to diminish cytokine signaling. These treatments can lead to inadvertent immune suppression and may increase the risk of viral infection. Tyrosine kinase 2 (TYK2) is a JAK family member required for efficient type I interferon (IFN-α/β) signaling. We report here that selective TYK2 inhibition preferentially blocked potentially detrimental type I IFN signaling, whereas IFN-λ–mediated responses were largely preserved. In contrast, the clinically used JAK1/2 inhibitor baricitinib was equally potent in blocking IFN-α/β– or IFN-λ–driven responses. Mechanistically, we showed that epithelial cells did not require TYK2 for IFN-λ–mediated signaling or antiviral protection. TYK2 deficiency diminished IFN-α–induced protection against lethal influenza virus infection in mice but did not impair IFN-λ–mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors used in place of broadly acting JAK1/2 inhibitors may represent a superior treatment option for type I interferonopathies to counteract inflammatory responses while preserving antiviral protection mediated by IFN-λ.

scholarly journals Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise

2021 ◽  
Author(s):  
Silvio Danese ◽  
Laurent Peyrin-Biroulet
Keyword(s):  
Inflammatory Bowel Disease ◽  
Tyrosine Kinase ◽  
Bowel Disease ◽  
Inflammatory Diseases ◽  
Janus Kinase ◽  
Type I ◽  
Tyrosine Kinase 2 ◽  
Immune Mediated ◽  
Inflammatory Bowel

Abstract Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.

scholarly journals TYK2: An Upstream Kinase of STATs in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1728 ◽  
Author(s):  
Katharina Wöss ◽  
Natalija Simonović ◽  
Birgit Strobl ◽  
Sabine Macho-Maschler ◽  
Mathias Müller
Keyword(s):  
Protein Tyrosine Kinase ◽  
Inflammatory Responses ◽  
Immune Surveillance ◽  
Pharmacological Intervention ◽  
Cytokine Signaling ◽  
Loss Of Function ◽  
Signal Transducers ◽  
Protein Levels ◽  
Tyrosine Kinase 2 ◽  
Upstream Kinase

In this review we concentrate on the recent findings describing the oncogenic potential of the protein tyrosine kinase 2 (TYK2). The overview on the current understanding of TYK2 functions in cytokine responses and carcinogenesis focusses on the activation of the signal transducers and activators of transcription (STAT) 3 and 5. Insight gained from loss-of-function (LOF) gene-modified mice and human patients homozygous for Tyk2/TYK2-mutated alleles established the central role in immunological and inflammatory responses. For the description of physiological TYK2 structure/function relationships in cytokine signaling and of overarching molecular and pathologic properties in carcinogenesis, we mainly refer to the most recent reviews. Dysregulated TYK2 activation, aberrant TYK2 protein levels, and gain-of-function (GOF) TYK2 mutations are found in various cancers. We discuss the molecular consequences thereof and briefly describe the molecular means to counteract TYK2 activity under (patho-)physiological conditions by cellular effectors and by pharmacological intervention. For the role of TYK2 in tumor immune-surveillance we refer to the recent Special Issue of Cancers “JAK-STAT Signaling Pathway in Cancer”.

Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Amira Alkharusi ◽  
Mercedes Mirecki-Garrido ◽  
Zuheng Ma ◽  
Fahad Zadjali ◽  
Amilcar Flores-Morales ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Type I ◽  
Suppressor Of Cytokine Signaling ◽  
Β Cell ◽  
Diabetes In Mice ◽  
Socs Proteins ◽  
Stat Pathway

AbstractDiabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity.The elevated sensitivity of SOCS2We show that 6-month-old SOCS2Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.

scholarly journals Molecular Cloning and Expression Analysis of Three Suppressors of Cytokine Signaling Genes (SOCS5, SOCS6, SOCS7) in the Mealworm Beetle Tenebrio molitor

Insects ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 76 ◽  
Author(s):  
Bharat Patnaik ◽  
Bo Kim ◽  
Yong Jo ◽  
In Bang
Keyword(s):  
Functional Characterization ◽  
Tenebrio Molitor ◽  
Janus Kinase ◽  
Cloning And Expression ◽  
Cytokine Signaling ◽  
Type I ◽  
Growth Factor Signaling ◽  
Expression Levels ◽  
Mealworm Beetle ◽  
Suppressors Of Cytokine Signaling

Suppressors of cytokine signaling (SOCS) influence cytokine and growth factor signaling by negatively regulating the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway to maintain homeostasis during immune responses. However, functional characterization of SOCS family members in invertebrates is limited. Here, we identified and evaluated three SOCS genes (type I sub-family) in the mealworm beetle Tenebrio molitor. The full-length open reading frames (ORFs) of TmSOCS5, TmSOCS6, and TmSOCS7 comprised of 1389, 897, and 1458 nucleotides, encoding polypeptides of 462, 297, and 485 amino acids, respectively. The SH2 and SOCS box domains of the TmSOCS C-terminal region were highly conserved. Phylogenetic analysis revealed that these SOCS genes were clustered within the type I subfamily that exhibits the highest amino acid identity with Tribolium castaneum SOCS genes. Contrary to TmSOCS7 expression, the expression levels of TmSOCS5 and TmSOCS6 were lower in the larval, pupal, and adult stages. In larvae and adults, the expression levels of TmSOCS5 and TmSOCS6 were highest in the hemocytes and ovaries, respectively. SOCS transcripts were also highly upregulated in the hemocytes of T. molitor larvae within 3–6 h post-infection with the fungus Candida albicans. Collectively, these results provide valuable information regarding the involvement of TmSOCS type-I subfamily in the host immune response of insects.

Interleukin-6 and interleukin-11: same same but different

2013 ◽  
Vol 394 (9) ◽  
pp. 1145-1161 ◽  
Author(s):  
Christoph Garbers ◽  
Jürgen Scheller
Keyword(s):  
Neuronal Development ◽  
Inflammatory Diseases ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Cytokine Signaling ◽  
Downstream Signaling ◽  
Mitogen Activated Protein ◽  
Β Receptor ◽  
Redundant Functions

Abstract The pleiotropic physiological functions of interleukin (IL-)6 type cytokines range from embryonic development and tissue homoeostasis to neuronal development and T cell differentiation. In contrast, imbalance of the well-controlled cytokine signaling network leads to chronic inflammatory diseases and cancer. IL-6 and IL-11 both signal through a homodimer of the ubiquitously expressed β-receptor glycoprotein 130 (gp130). Specificity is gained through an individual IL-6/IL-11 α-receptor, which does not directly participate in signal transduction, although the initial cytokine binding event to the α-receptor leads to the final complex formation with the β-receptors. Both cytokines activate the same downstream signaling pathways, which are predominantly the mitogen-activated protein kinase (MAPK)-cascade and the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway. However, recent studies have highlighted divergent roles of the two related cytokines. Here, we will discuss how the biochemical similarities are translated into unique and non-redundant functions of IL-6 and IL-11 in vivo and illustrate strategies for cytokine-specific therapeutic intervention.

scholarly journals Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jérôme Hadjadj ◽  
Marie-Louise Frémond ◽  
Bénédicte Neven
Keyword(s):  
Inflammatory Diseases ◽  
Cytokine Signaling ◽  
Type I ◽  
Jak Inhibitors ◽  
Front Line ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Monogenic Diseases ◽  
Excessive Secretion ◽  
Stat Pathway

Among inborn errors of immunity (IEIs), some conditions are characterized by inflammation and autoimmunity at the front line and are particularly challenging to treat. Monogenic diseases associated with gain-of-function mutations in genes critical for cytokine signaling through the JAK-STAT pathway belong to this group. These conditions represent good candidates for treatment with JAK inhibitors. Type I interferonopathies, a group of recently identified monogenic auto-inflammatory diseases characterized by excessive secretion of type I IFN, are also good candidates with growing experiences reported in the literature. However, many questions remain regarding the choice of the drug, the dose (in particular in children), the efficacy on the various manifestations, the monitoring of the treatment, and the management of potent side effects in particular in patients with infectious susceptibility. This review will summarize the current experiences reported and will highlight the unmet needs.

scholarly journals LGP2 binds to PACT to regulate RIG-I– and MDA5-mediated antiviral responses

2019 ◽  
Vol 12 (601) ◽  
pp. eaar3993 ◽  
Author(s):  
Raul Y. Sanchez David ◽  
Chantal Combredet ◽  
Valérie Najburg ◽  
Gael A. Millot ◽  
Guillaume Beauclair ◽  
...  
Keyword(s):  
Rna Silencing ◽  
Rna Binding ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Type I ◽  
Double Stranded Rna ◽  
Rna Molecules ◽  
Protein Protein Interaction ◽  
Antiviral Responses ◽  
Inducible Gene

The retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs) RIG-I, MDA5, and LGP2 stimulate inflammatory and antiviral responses by sensing nonself RNA molecules produced during viral replication. Here, we investigated how LGP2 regulates the RIG-I– and MDA5-dependent induction of type I interferon (IFN) signaling and showed that LGP2 interacted with different components of the RNA-silencing machinery. We identified a direct protein-protein interaction between LGP2 and the IFN-inducible, double-stranded RNA binding protein PACT. The LGP2-PACT interaction was mediated by the regulatory C-terminal domain of LGP2 and was necessary for inhibiting RIG-I–dependent responses and for amplifying MDA5-dependent responses. We described a point mutation within LGP2 that disrupted the LGP2-PACT interaction and led to the loss of LGP2-mediated regulation of RIG-I and MDA5 signaling. These results suggest a model in which the LGP2-PACT interaction regulates the inflammatory responses mediated by RIG-I and MDA5 and enables the cellular RNA-silencing machinery to coordinate with the innate immune response.

scholarly journals Essential Kinases and Transcriptional Regulators and Their Roles in Autoimmunity

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 145 ◽  
Author(s):  
Deng ◽  
Bellanti ◽  
Zheng
Keyword(s):  
Autoimmune Diseases ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Transcriptional Regulators ◽  
Janus Kinase ◽  
Orphan Receptor ◽  
Regulatory Cells ◽  
Biological Responses ◽  
Tyrosine Kinase 2 ◽  
Transcriptional Regulatory

Kinases and transcriptional regulators are fundamental components of cell signaling that are expressed on many types of immune cells which are involved in secretion of cytokines, cell proliferation, differentiation, and apoptosis. Both play important roles in biological responses in health as well as in illnesses such as the autoimmune diseases which comprise at least 80 disorders. These diseases are caused by complex genetic and environmental interactions that lead to a breakage of immunologic tolerance and a disruption of the balance between self-reactive cells and regulatory cells. Kinases or transcriptional regulatory factors often have an abnormal expression in the autoimmune cells that participate in the pathogenesis of autoimmune disease. These abnormally expressed kinases or transcriptional regulators can over-activate the function of self-reactive cells to produce inflammatory cytokines or down-regulate the activity of regulatory cells, thus causing autoimmune diseases. In this review we introduce five kinds of kinase and transcriptional regulator related to autoimmune diseases, namely, members of the Janus kinase (JAK) family (JAK3 and/or tyrosine kinase 2 (TYK2)), fork head box protein 3 (Foxp3), the retinoic acid-related orphan receptor gamma t (RORγt), and T-box expressed in T cells (T-bet) factors. We also provide a mechanistic insight into how these kinases and transcriptional regulators affect the function of the immune cells related to autoimmune diseases, as well as a description of a current drug design targeting these kinases and transcriptional regulators. Understanding their exact role helps offer new therapies for control of the inflammatory responses that could lead to clinical improvement of the autoimmune diseases.

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

2017 ◽  
Vol 77 (2) ◽  
pp. 175-187 ◽  
Author(s):  
Kenneth F Baker ◽  
John D Isaacs
Keyword(s):  
Lupus Erythematosus ◽  
First Generation ◽  
Inflammatory Diseases ◽  
Cellular Adhesion ◽  
Janus Kinase ◽  
Type I ◽  
Jak Inhibitors ◽  
T Helper 17 ◽  
Immune Mediated ◽  
Sphingosine 1 Phosphate

The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

scholarly journals Oncogenic TYK2P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade

Haematologica ◽  
2022 ◽  
Author(s):  
Katharina Woess ◽  
Sabine Macho-Maschler ◽  
Dorette S. Van Ingen Schenau ◽  
Miriam Butler ◽  
Caroline Lassnig ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
De Novo ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Treatment Options ◽  
Specific Inhibitor ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Tyrosine Kinase 2

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase/signal transducer and activator of transcription pathway, which is central in cytokine signaling. Previously, germline TYK2 mutations have been described in two patients developing de novo T-cell acute lymphoblastic leukemias (T-ALLs) or precursor B-ALLs. The mutations (P760L and G761V) are located within the regulatory pseudokinase domain and lead to constitutive activation of TYK2. We demonstrate the transformation capacity of TYK2P760L in hematopoietic cell systems including primary bone marrow cells. In vivo engraftment of TYK2P760L-expressing cell lines led to development of leukemia. A kinase inhibitor screen uncovered that oncogenic TYK2 acts synergistically with the PI3K/AKT/mTOR and CDK4/6 pathways. Accordingly, the TYK2-specific inhibitor deucravacitinib (BMS986165) reduces cell viability of TYK2P760Ltransformed cell models and ex vivo cultured TYK2P760L-mutated patient-derived xenograft cells most efficiently when combined with mTOR or CDK4/6 inhibitors. Our study thereby pioneers novel treatment options for patients suffering from TYK2-driven acute leukemia.

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