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Relationship: 2024
Title
Inhibition of JAK3 leads to STAT5 inhibition
Upstream event
Downstream event
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Inhibition of JAK3 leading to impairment of T-Cell Dependent Antibody Response | adjacent | High | High | Brendan Ferreri-Hanberry (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
Nelson et al. reported that a membrane proximal region of the interleukin-2 receptor gamma c chain sufficient for Jak kinase activation and induction of proliferation in T cells (Nelson, et al. 1996). Furthermore, Kirken RA et al. demonstrated that activation of JAK3, but not JAK1, is critical for IL-2-induced proliferation and STAT5 recruitment by a COOH-terminal region of the IL-2 receptor beta-chain (Kirken, et al. 1995). Therefore, STAT activation is regulated by JAK via phosphorylation. Thus, JAK inhibitors commonly interfere with STAT activation.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
The fluorescence intensity of phospho-STAT5 in CD3-positive lymphocytes was reportedly increased upon incubation of peripheral blood with IL-2. Peficitinib is a pan-JAK family inhibitor that can inhibit STAT5 phosphorylation in a concentration-dependent manner with a mean IC50 of 124 nM (101 and 147 nM for two rats). The effect of peficitinib on IL-2 stimulated STAT5 phosphorylation in human peripheral T cells has been evaluated. In parallel with results obtained from rats, the fluorescence intensity of phospho-STAT5 in CD3-positive lymphocytes increased in human peripheral blood after the addition of IL-2, but peficitinib inhibited STAT5 phosphorylation in a dose-dependent manner with a mean IC50 of 127 nM in human lymphocytes (Gianti and Zauhar 2015).
Response-response Relationship
MIE:
Dose-response analysis of the effects of RB1 on JAK3 kinase activity showed that RB1 inhibits JAK3 kinase activity in a dose-dependent manner with an IC50 value of 40 nM, without inhibiting JAK1, JAK2, or TYK2 (Pei, et al. 2018).
Normal rats were administered peficitinib at 10 and 20 mg/kg. Thirteen hours later, the animals were bled and STAT5 phosphorylation was assessed. IL-2-induced STAT5 phosphorylation of CD3-positive lymphocytes in peripheral blood from the peficitinib-treated rats was suppressed by 37% at a dose of 10 mg/kg and 78% at 20 mg/kg (Gianti and Zauhar 2015).
Time-scale
The enzymatic activities against JAK1, JAK2, JAK3, and TYK2 were immediately tested in CTLL-2 cells using a Caliper Mobility Shift Assay with an ATP concentration at Km (Pei, et al. 2018). CTLL-2 cells were treated with 10 µM adenosine (plus coformycin) for 15 min at 37°C and then stimulated with IL-2 (10 U/mL) for different lengths of time (5 min-12 h). Adenosine dramatically decreased dose-dependent STAT5A/B tyrosine phosphorylation in response to IL-2 over the entire 12 h time course (Zhang, et al. 2004).