Article

Janus kinases in immune cell signaling

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: 12.91). 04/2009; 228(1):273-87. DOI: 10.1111/j.1600-065X.2008.00754.x
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
153 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Immunobiology 01/2015; DOI:10.1016/j.imbio.2015.01.008 · 3.18 Impact Factor
  • Source
    • "The JAK tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) are activated by cytokine receptor ligation leading to the subsequent phosphorylation and activation of STAT transcription factors (Ghoreschi et al., 2009). Activating JAK mutations have been identified in a range of human lymphoid and myeloid malignancies including pediatric and Down-syndromeassociated precursor-B-ALL (James et al., 2005; Mullighan et al., 2009b; Van Roosbroeck et al., 2011), and these JAK2 mutations are strong drivers of cellular transformation (Carron et al., 2000; Marty et al., 2010; Mullally et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.
    Cell Reports 11/2013; 5(4). DOI:10.1016/j.celrep.2013.10.038 · 7.21 Impact Factor
  • Source
    • "The JAK family comprises four members—JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2)—and cytokine receptors may use various JAK combinations to transmit cellular signals (Murray, 2007). Studies in knockout mice have shown that deletion of these kinases can result in embryonic lethality, immunodeficiency , or impaired immune cell signaling and development (Shuai and Liu, 2003; Ghoreschi et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens which allow maximum therapeutic benefit with minimum toxicity. The preclinical pharmacokinetic/pharmacodynamic (PK/PD) profile of tofacitinib, an oral Janus kinase (JAK) inhibitor, in a mouse collagen-induced arthritis (mCIA) model was compared with clinical PK/PD data from patients with rheumatoid arthritis (RA). Preclinical evaluations included target modulation and PK/PD modeling based on continuous subcutaneous infusion or oral once- or twice daily (BID) dosing paradigms in mice. The human PK/PD profile was obtained from pooled data of four Phase 2 studies in patients with RA, and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment (1-15 mg BID). In mCIA, the main driver of efficacy was inhibition of cytokine receptor signaling mediated by JAK1 heterodimers, but not JAK2 homodimers, and continuous daily inhibition was not required to maintain efficacy. Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm, with a total steady-state plasma concentration achieving 50% of the maximal response (Cave50) of about 100 nM. Tofacitinib potency (ED50) in clinical studies was approximately 3.5 mg BID (90% confidence interval: 2.3, 5.5) or total Cave50 of about 40 nM, derived using disease activity scores from patients with RA. The collective clinical and preclinical data indicated the importance of Cave as a driver of efficacy, rather than maximum or minimum plasma concentration (Cmax or Cmin), where Cave50 values were within approximately 2-fold of each other.
    Journal of Pharmacology and Experimental Therapeutics 11/2013; 348(1). DOI:10.1124/jpet.113.209304 · 3.86 Impact Factor

Preview

Download
1 Download
Available from

Similar Publications