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Yasuhiro Yoshida (1) Takao Ashikaga (1) Tomoki Fukuyama (1) Ken Goto (1) Shinko Hata (1) Shigeru Hisada (1) Shiho Ito (1) Hiroyuki Komatsu (1) Sumie Konishi (1) Tadashi Kosaka (1) Kiyoshi Kushima (1) Shogo Matsumura (1) Takumi Ohishi (1) Yasuharu Otsubo (1) Junichiro Sugimoto (1)
(1) AOP Working Group, Testing Methodology Committee, The Japanese Society of Immunotoxicology
Corresponding author: Yasuhiro Yoshida (firstname.lastname@example.org)
Point of Contact
Yasuhiro Yoshida (email point of contact)
- Takumi Ohishi
- Yasuhiro Yoshida
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite||Under Development||1.74||Included in OECD Work Plan|
This AOP was last modified on September 24, 2020 11:08
|Inhibition of JAK3||September 18, 2020 02:05|
|Blockade of STAT5 phosphorylation||September 18, 2020 02:05|
|Suppression of STAT5 binding to cytokine gene promoters||September 18, 2020 02:06|
|Suppression of IL-4 production||September 18, 2020 02:06|
|Impairment of T-cell dependent antibody response||September 15, 2020 21:32|
|Inhibition of JAK3 leads to STAT5 inhibition||September 18, 2020 03:52|
|STAT5 inhibition leads to Suppression of STAT5 binding||September 18, 2020 03:49|
|Suppression of STAT5 binding leads to Suppression of IL-4 production||September 18, 2020 03:50|
|Suppression of IL-4 production leads to Impairment, TDAR||September 18, 2020 03:51|
|PF-06651600 (CAS No：1792180-81-4),||September 15, 2020 05:38|
|RB1||September 15, 2020 05:38|
Signal transduction between immune-related cells depends in many cases on cytokines and takes place via cell surface cytokine receptors as well as direct cell-to-cell interaction. Cytokines influence the movement, proliferation, differentiation, and activation of lymphocytes and other leukocytes in a variety of ways.
Some receptors for cytokines require and activation step through a Janus-kinase (JAK)/Signal Transducers and Activator of Transcription (STAT) system. When cytokine binds to its specific cytokine receptors, the cytokine receptors form dimers, which more closely resemble the JAK molecules. The JAK then activates to phosphorylate adjacent cytokine receptors. STATs bind to the phosphorylated sites of the receptors and are then phosphorylated by the activated JAK. The phosphorylated STAT is dimerized to be translocated into nucleus and bind to promoter regions of cytokine genes, which starts transcription of cytokine genes in the nucleus.
In mammals, four JAK families of enzymes (JAK1, JAK2, JAK3, TYK2) and seven STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) are utilized by more than 50 cytokines and growth factors to mediate intracellular signaling. In particular, pro-inflammatory cytokines such as interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, IL-6, IL-13, IL-21 and IL-23 have been implicated in inflammatory diseases that utilize the JAK pathway. In addition, TH2 derived cytokines, including IL-31 and thymic stromal lymphopoietin (TSLP), are ligands for murine and human sensory nerves and have a critical function that evokes itchiness. Because these cytokines also interact with JAK, several JAK-inhibitors have received a lot of attention recently as a therapeutic agent for major inflammatory diseases and pruritic diseases.
This proposed AOP consists of JAK3 inhibition as a MIE, blockade of STAT5 phosphorylation as a KE1, suppression of STAT5 binding to the promoter regions of cytokine genes as a KE2, suppression of IL-4 production as a KE3, and suppression of T cell-dependent antibody response (TDAR) as an AO. This AOP especially focuses on the inhibition of JAK3, which is required for signal transduction by cytokines through the common gamma (γ) chain of the interleukin receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. In this proposed AOP, JAK3 selective inhibitors (e.g. PF-06651600 (CAS No：1792180-81-4), RB1) are stressors. Upon the phosphorylation of STAT5 by JAK3, it makes a homo-dimer to translocate to nucleus and induce gene expression such as IL-4. Therefore, JAK3 inhibition leads to the suppression of STAT5 binding to the promoter regions of cytokine genes and the subsequent suppression of IL-4 production. In this way, JAK/STAT regulation plays an important role in TDAR. TDAR is frequently affected under immunosuppressive conditions and is a major endpoint in many preclinical immunotoxicity studies.
Although there are numerous stressors that inhibit JAK3 activity, this AOP is based on immunosuppression caused by recently developed, highly selective JAK3 inhibitors PF-06651600 and RB1, about which a significant body of scientific literature has been published.
We look forward to future amendments to this AOP with up-to-date information on other stressors, which will clarify the link between inhibition of JAK activity and impairment of TDAR.
Summary of the AOP
Events: Molecular Initiating Events (MIE)
|Sequence||Type||Event ID||Title||Short name|
|MIE||1715||Inhibition of JAK3||Inhibition of JAK3|
|KE||1716||Blockade of STAT5 phosphorylation||STAT5 inhibition|
|KE||1717||Suppression of STAT5 binding to cytokine gene promoters||Suppression of STAT5 binding|
|KE||1718||Suppression of IL-4 production||Suppression of IL-4 production|
|AO||1719||Impairment of T-cell dependent antibody response||Impairment, TDAR|
Relationships Between Two Key Events
(Including MIEs and AOs)
|Inhibition of JAK3 leads to STAT5 inhibition||adjacent||High||High|
|STAT5 inhibition leads to Suppression of STAT5 binding||adjacent||High||High|
|Suppression of STAT5 binding leads to Suppression of IL-4 production||adjacent||High||High|
|Suppression of IL-4 production leads to Impairment, TDAR||adjacent||High||High|
Life Stage Applicability
|All life stages||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
Overall Assessment of the AOP
JAKs are a family of nonreceptor tyrosine kinase and consists of four members: JAK1, JAK2, JAK3, and Tyk2 (1-Johnston-1994). All four members mediate signals initiated by cytokines through interactions with receptors for IL-2, IL-5, IL-7, IL-9, and IL-15 via the common γ chain (2-Witthuhn-1994). Different studies have shown that JAK3 is widely expressed in different organs (2-Witthuhn-1994). Previous studies with IL-2Rγ-null mice showed that JAK3 is related to the development of spontaneous inflammatory bowel disease (IBD) symptoms (3-Miyazaki-1994). Moreover, abnormal activation of JAK3 was associated with human hematological (4-Ihle-1997), indicating that a tight balance of its activity was essential for normal hematopoietic development.
Although JAK1, JAK2, and Tyk2 are each widely expressed, JAK3 is predominantly expressed in hematopoietic cells and is known to associate only with the common γ (γc) chain of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors (5-Nosaka-1995). IL-4 is a very well-known cytokine that plays a crucial role in the polarization of naïve T cells to type 2 helper T cells. It plays a major role in the growth and proliferation of many immune cells such NK and T cells (6-Dhupkar-2017). Homozygous mutant mice in which the JAK3 gene had been disrupted were generated by gene targeting. JAK3-deficient mice had profound reductions in thymocytes and severe B cell and T cell lymphopenia similar to severe combined immunodeficiency disease (SCID), and the residual T cells and B cells were functionally deficient. Thus, JAK3 plays a critical role in γc signaling and lymphoid development.
Domain of Applicability
This proposed AOP involves inhibition of JAK activity leading to suppression of TDAR and is not dependent on life stage, sex, or age. Since JAK3 inhibitors (PF-06651600, RB1) are currently under a phase 2 clinical evaluation to treat rheumatoid arthritis, the AOP appears to be applicable to all life stages. Since JAK3 inhibitor-induced outcomes in humans are mimicked by similar responses in a variety of animal models, including non-human primates and rodents, immunosuppression induced by inhibition of JAK3 activity is considered to occur across a variety of mammalian species. For example, PF-06651600 reduces paw swelling with an unbound EC50 of 169 nM in the rat adjuvant-induced arthritis. Similarly, PF-06651600 significantly reduces disease severity in the experimental autoimmune encephalomyelitis (EAE) mouse model at 30 or 100 mg/kg or prophylactically at 20 and 60 mg/kg. Then, PF-06651600 is going to clinical trials (7-Telliez-2016).
Essentiality of the Key Events
MIE and later events: JAK3-knockout (KO) mice
JAK3 was initially identified (1-Johnston-1994,2-Witthuhn-1994) in studies to identify the JAK family member that was involved in the signaling of a group of cytokines that shared in common the utilization of the γc chain first identified in the interleukin 2 (IL-2) receptor complex. It was subsequently demonstrated that JAK3 physically associates with the γc chain and is activated in a receptor complex that also contains JAK1, which associates with the ligand specific alpha or beta chain of the receptors (3-Miyazaki-1994).JAK3 is somewhat unique within the JAK family in that it is predominantly expressed in hematopoietic cells and is only activated in the responses to cytokines that use the γc chain (4-Ihle-1997). The phenotype of the JAK3 deletion mice was quite striking and consisted of a range of deficiencies which collectively constituted SCID (5-Nosaka-1995,8-Thomis-1995). At the same time, two groups identified individuals that lacked JAK3 and exhibited somatically acquired SCID (9-Macchi-1995,10-Russell-1995). One of the most striking components of the phenotype is the dramatic reduction seen in both the T and B cell lineages. Comparable reductions are seen in mice that lack IL-7 (11-von Freeden-Jeffry-1995), the IL-7 receptor alpha chain (12-Peschon-1994), or the γc chain. In spite of the reduced numbers, the cells that do develop are phenotypically normal. These results are consistent with the hypothesis that activation of JAK3 give it a critical role in the expansion but not the differentiation of early lymphoid lineage-committed cells. In addition to the reduced numbers, the differentiated lymphoid cells that are generated fail to respond to the spectrum of cytokines that utilize the γc chain and activate JAK3 normally.
Primary immunodeficiencies (PIDs) are inborn errors that cause developmental and/or functional defects in the immune system (13-Picard-2015). Most frequently rare and monogenic, PIDs present clinically with a broad array of phenotypes including increased susceptibility to infection. One of the most deadly categories of PID is SCID, which is invariably caused by severe developmental and/or functional defects of T lymphocytes, but may also present with variable defects of B and/or Natural Killer (NK) cells. The B6.Cg-Nr1d1tm1Ven/LazJ mouse line harbors a spontaneous mutation in JAK3, which generates an SCID phenotype (14-Robinette-2018).
KE1: STAT5-KO mice
STAT5 plays a major role in regulating vital cellular functions such as proliferation, differentiation, and apoptosis of hematopoietic and immune cells (15-Rani-2016,16-Wittig-2005). STAT5 is activated by phosphorylation of a single tyrosine residue (Y694 in STAT5) and negatively regulated by dephosphorylation. A wide variety of growth factors and cytokines can activate STAT5 through the JAK-STAT pathway. The activation of STAT5 is transient and tightly regulated in normal cells (17-Quezada Urban-2018).
The following phenotypes are observed in STAT5-KO mice:
The transcription factor STAT5 is expressed in all lymphocytes and plays a key role in multiple aspects of lymphocyte development and function (18-Owen-2017). STAT5 was initially identified as a transcription factor activated by prolactin in mammary gland epithelial cells (19-Schmitt-Ney-1992,20-Wakao-1992). Subsequent studies identified STAT5 binding activity in T cells (21-Beadling-1994), and it was later established that STAT5 was expressed in multiple cell types and activated by a number of cytokines, including the common γc-dependent cytokines interleukin 2 (IL2), IL4, IL7, IL13, and IL15 (22-Lin-1995).
STAT5 in T-cell development
The observation that STAT5 is activated by multiple cytokines in T cells suggested that it might play a critical role in the development or function (or both) of these cells. Disruption of Stat5a or Stat5b genes alone resulted in relatively modest phenotypes; for example, Stat5a-/- mice had defects in mammary gland development and lactation while Stat5b-/- mice had defects in response to growth hormone in male mice and natural killer cell proliferation (23-Imada-1998,24-Liu-1997). To determine whether combined deletion of Stat5a and Stat5b might result in more profound immunodeficiencies, subsequent studies deleted the first coding exons of both Stat5a and Stat5b. This intervention resulted in the production of truncated forms of STAT5a and STAT5b that acted as functional hypomorphs. These mice too had surprisingly mild defects in lymphocyte development, although T cells were grossly dysfunctional, as they could no longer proliferate in response to IL-2 (25-Moriggl-1999,26-Teglund-1998). Finally, complete deletion of Stat5a and Stat5b using
T-cell development is mainly regulated by JAK-STAT system, and JAK3 deficiency in T cells is known to induce multiple types of immunosuppression, including TDAR.
JAK3-deficient mice had profound reductions in thymocytes and severe B cell and T cell lymphopenia similar to SCID disease, and the residual T cells and B cells were functionally deficient (12-Peschon-1994).
Mice lacking JAK3 also showed a severe block in B cell development at the pre-B stage in the bone marrow. In contrast, although the thymuses of these mice were small, T cell maturation progressed relatively normally. In response to mitogenic signals, peripheral T cells in JAK3-deficient mice did not proliferate and secreted small amounts of IL-4. These data demonstrate that JAK3 is critical for the progression of B cell development in the bone marrow and for the functional competence of mature T cells (5-Nosaka-1995).
Furthermore, the abnormal architecture of lymphoid organs suggested the involvement of JAK3 in the function of epithelial cells. T cells developed in the mutant mice did not respond to either IL-2, IL-4, or IL-7 (29-Ito-2017).
Specific JAK3 inhibitor PF-06651600 or RB1, which selectively inhibited JAK3 with an over 100-fold preference over JAK2, JAK1, and TYK2 in the kinase assay, displayed reduced inflammation and associated pathology in collagen-induced-arthritis mice. Importantly, with PF-06651600 or RB1 administration, pro-inflammatory cytokines and JAK3 and STATs phosphorylation decreased in mice, suggesting that the inhibition of JAK3/STAT signaling was closely correlated with induction of multiple types of immunosuppression, including TDAR.
KER1 (MIE=>KE 1)：
Treatment of highly selective JAK3 inhibitors (PF-06651600 or RB1) clearly suppresses the complex formation of STAT5 in the nucleus. IL-2 have been demonstrated to stimulate STAT5 and induce tyrosine phosphorylation of STAT5 (35-Wakao-1995). Highly-selective JAK3 inhibitor RB1 inhibited the phosphorylation of STAT5 elicited by IL-2 at IC50 value of 31 nM in the raw peripheral blood mononuclear cells (PBMCs) of humans. PBMCs were isolated from the buffy coats of healthy volunteers using density gradient centrifugation on Lymphoprep. Cells were cultured in complete RPMI 1640 medium (containing 10% foetal bovine serum, 100 mg/ml streptomycin and 100 U/ml penicillin) plus 10 μg/ml lectin phytohemagglutinin (PHA) for 3 days and then treated with either recombinant human IL-6 (400 ng/ml), recombinant human IL-2 (100 ng/ml), or recombinant human GM-CSF (50 ng/ml) at 37 °C for 20 min. To terminate the stimulation, cells were fixed with Lyse/Fix Buffer and then incubated with 100% methanol for 30 minutes; cells were incubated with anti-pSTAT3 and anti-CD4 Abs, or anti-pSTAT5 and anti-CD4 Abs at 4 °C overnight, washed twice with PBS, and analysed with an flow cytometer (36-Ju-2011).
Fluorescence intensity for phospho-STAT5 in CD3-positive lymphocytes increased upon incubation of peripheral blood with IL-2. Peficitinib inhibited STAT5 phosphorylation in a concentration-dependent manner with a mean IC50 of 124 nM (101 and 147 nM for two rats). Additionally, the effect of peficitinib on IL-2 stimulated STAT5 phosphorylation in human peripheral T-cells was evaluated. Paralleling results in rats, the fluorescence intensity of phospho-STAT5 in CD3-positive lymphocytes increased in human peripheral blood after adding IL-2, but peficitinib inhibited STAT5 phosphorylation in a concentration-dependent manner with a mean IC50 of 127 nM in human lymphocytes (29-Ito-2017).
KER2 (KE1 =>KE 2)：
STAT5 could be activated and phosphorylated by cytokines such as IL-2 and IL-15. Tyrosine phosphorylation of STAT5 is important for dimerization of STAT5 (35-Wakao-1995). Dimer of STAT5 has an identical DNA binding specificity and immunoreactivity.
KER3：(KE2 =>KE 3)：
STAT5 is phosphorylated by the JAK kinases, allowing its dimerization and translocation into the nucleus where it can bind to its specific DNA binding sites. Electrophoretic mobility shift assay (EMSA) showed that IL-2 activation induced STAT5 dimerization and DNA binding to gamma interferon-activated site (GAS) motif in IL-4 receptor alpha promoter region (37-John-1999). Furthermore, mononuclear cells cultured with dex (dexamethazone) (10-6M) inhibited STAT5 DNA binding. EMSAs showed that Dex inhibited STAT5 DNA binding in dose-dependent fashion, including concentrations of dex (10-8M～10-7M) (38-Bianchi-2000).
In T cells, binding of IL-4 to its receptor induces proliferation and differentiation into Th2 cells. Th2 cells provide help for B cells and promote class switching from IgM to IgG1 and IgE. Therefore, the suppression of IL-4 production leads to the impairment of TDAR.
In the human T-B cell co-culture stimulated with anti-CD3 monoclonal antibody, calcineurin inhibitors (CNIs) of FK506 and CsA lowered the levels of T-cell cytokines including IL-2 and IL-4 and inhibited IgM and IgG productions with a dose-dependent manner (39-Heidt-2010).
These results show the quantitative relationships between the inhibition of IL-4 by specific antibodies or CNI and suppression of antibody production.
Considerations for Potential Applications of the AOP (optional)
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