Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells.
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 (gamma(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 gamma(c). AG-490 also inhibited IL-2-mediated proliferative growth in human T cells with an IC50) = 25 microM 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.
Kirken
R A
RA
IRSP, SAIC Frederick, Frederick Cancer Research and Development Center, Maryland, USA. rkirken@farmr1.med.uth.tmc.edu
Erwin
R A
RA
Taub
D
D
Murphy
W J
WJ
Behbod
F
F
Wang
L
L
Pericle
F
F
Farrar
W L
WL
D000818:Animals; D000941:Antigens / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology*
D000941:Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D014157:Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3