Janus kinases in immune cell signaling. Immunol Rev

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Immunological Reviews (Impact Factor: 10.12). 04/2009; 228(1):273-87. DOI: 10.1111/j.1600-065X.2008.00754.x
Source: PubMed


The Janus family kinases (Jaks), Jak1, Jak2, Jak3, and Tyk2, form one subgroup of the non-receptor protein tyrosine kinases. They are involved in cell growth, survival, development, and differentiation of a variety of cells but are critically important for immune cells and hematopoietic cells. Data from experimental mice and clinical observations have unraveled multiple signaling events mediated by Jaks in innate and adaptive immunity. Deficiency of Jak3 or Tyk2 results in defined clinical disorders, which are also evident in mouse models. A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome. By contrast, complete deletion of Jak1 or Jak2 in the mouse are not compatible with life and, unsurprisingly, do not have counterparts in human disease. However, activating mutations of each of the Jaks are found in association with malignant transformation, the most common being gain-of-function mutations of Jak2 in polycythemia vera and other myeloproliferative disorders. Our existing knowledge on Jak signaling pathways and fundamental work on their biochemical structure and intracellular interactions allow us to develop new strategies for controlling autoimmune diseases or malignancies by developing selective Jak inhibitors, which are now coming into clinical use. Despite the fact that Jaks were discovered only a little more than a decade ago, at the time of writing there are 20 clinical trials underway testing the safety and efficacy of Jak inhibitors.

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    • "As shown in Fig. 2 A, TYK2-deficient cells displayed low levels of IFN-R1 surface expression, whereas IFN-R2, IFN-R1, and IFN-R2, which are not known to bind TYK2, were normally expressed (not depicted). We also assessed the expression of IL-10R2 and IL-12R1, which are constitutively associated with TYK2 (Ghoreschi et al., 2009; Casanova et al., 2012; Stark and Darnell, 2012). As expected, IL-10R2– and IL-12R1– deficient cells did not express the corresponding receptors. "
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    ABSTRACT: Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans. © 2015 Kreins et al.
    Full-text · Article · Aug 2015 · Journal of Experimental Medicine
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    • "An early event triggered by IL-21 engagement is the activation of the Janus kinase-(JAK-) 1 and JAK-3 that phosphorylate tyrosine residues the intracellular regions of the receptor chains [6] (Figure 1). These phosphorylated regions serve as docking sites for the SH2 domains of specific signal transducers and activators of transcription (STAT) proteins, including STAT-1, STAT-3, and, to a lesser extent, STAT-5 [7] [8]. "
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    ABSTRACT: Interleukin- (IL-) 21 is a pleiotropic cytokine that regulates the activity of both innate and specific immunity. Indeed, it costimulates T and natural killer (NK) cell proliferation and function and regulates B cell survival and differentiation and the function of dendritic cells. In addition, IL-21 exerts divergent effects on different lymphoid cell leukemia and lymphomas, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the neoplastic lymphoid cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanism involving the activation of NK and T or B cell responses. Moreover, IL-21’s antitumor activity can be potentiated by its combination with other immune-enhancing molecules, monoclonal antibodies recognizing tumor antigens, chemotherapy, or molecular targeted agents. Clinical phase I-II studies of IL-21 in cancer patients showed immune stimulatory properties, acceptable toxicity profile, and antitumor effects in a fraction of patients. In view of its tolerability, IL-21 is also suitable for combinational therapeutic regimens with other agents. This review will summarize the biological functions of IL-21, and address its role in lymphoid malignancies and preclinical and clinical studies of cancer immunotherapy.
    Full-text · Article · May 2015 · Journal of Immunology Research
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    • "In recent years, numerous studies have established that hyperactivation of the JAK/STAT signal pathway occurs in the synovium of RA patients and of animal models of arthritis, signifying an essential role of this signaling pathway in regulation of the inflammatory response (Mori et al., 2011). It is well known that JAKs associate with cytokine receptors and translate signals triggered by cytokine binding into intracellular responses (Ghoreschi et al., 2009). Recently it has been proposed that downregulation or inhibition of JAKs would effectually prevent cytokine signaling and thus treat RA; however, the precise role of JAK/STAT signaling in this disease remains unclear (Fridman et al., 2015). "
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    ABSTRACT: Histamine 4 receptor (H4R) is a novel target for the pharmacological modulation of histamine-mediated immune signals during inflammatory diseases. The purpose of this study was to assess the effects of the H4R agonist 4-methylhistamine dihydrochloride (4-MeH) and antagonist JNJ7777120 (JNJ) in the inflamed rat knee. Animals were fasted for 18 hours before a single dose of 4-MeH or JNJ (30 mg/kg) was administered intraperitoneally (i.p.), both followed by intra-articular (i.a) injection of LPS two hours later. Blood and synovial fluid were collected after a short incubation period and TNF-α, NF-kB, and IkB-α levels were measured via flow cytometry. Additionally, we assessed the effects of H4R engagement on the expression of IL-1β, TNF-α, and NF-kB mRNAs and the protein levels of TNF-α, NF-kB, JAK-1, and STAT-3 in the inflamed knee tissue. These results revealed increased TNF-α and NF-kB expression and decreased IkB-α levels in both the LPS alone and 4-MeH treated groups in whole blood and synovial fluid. Further, IL-1β, TNF-α, and NF-kB mRNA levels were significantly increased and western blot analysis confirmed increased expression of TNF-α, NF-kB, JAK-1, and STAT-3 in both LPS and 4-MeH treatment groups. Furthermore, these increases were completely inhibited in the inflamed knee tissue of the JNJ-treated group. Thus, the inhibition of inflammatory mediators and signaling pathways by the H4R antagonist JNJ suggests the anti-arthritic importance of this molecule.
    Full-text · Article · Jan 2015 · Immunobiology
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