Abstract
Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase required for T cell development and activated by cytokines that utilize the interleukin-2 (IL-2) receptor common gamma chain (γ(c)). Genetic inactivation of JAK3 is manifested as severe combined immunodeficiency disease (SCID) in humans and mice. These findings have suggested that JAK3 represents a pharmacological target to control certain lymphoid-derived diseases. Here we provide novel evidence that AG-490 potently inhibits the autokinase activity of JAK3 and tyrosine phosphorylation and DNA binding of signal transducer and activator of transcription 5a and 5b (STAT5a/b). Similar inhibitory effects were observed with other cytokines that use γ(c). AG-490 also inhibited IL-2- mediated proliferative growth in human T cells with an IC50 = 25 μM that was partially recoverable. Moreover, we demonstrate that this inhibitor prevented tetanus toxoid antigen-specific T cell proliferation and expansion but failed to block activation of Zap70 or p56Lck after anti-CD3 stimulation of human T cells. Taken together, these findings suggest that AG-490 inhibits the JAK3-mediated Type II signaling pathway but not the T cell receptor- derived Type I pathway and possesses therapeutic potential for T cell- derived pathologies such as graft-versus-host disease, allergy, and autoimmune disorders.
Original language | English (US) |
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Pages (from-to) | 891-899 |
Number of pages | 9 |
Journal | Journal of Leukocyte Biology |
Volume | 65 |
Issue number | 6 |
State | Published - 1999 |
Externally published | Yes |
Keywords
- Interleukin-2
- Kinase inhibitors
- Stats
- YAKs
ASJC Scopus subject areas
- Cell Biology