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 m anifested 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 obs erved with other cytokines that use gamma(c). AG-490 also inhibited IL-2-me diated proliferative growth in human T cells with an IC50 = 25 mu M that wa s partially recoverable. Moreover, we demonstrate that this inhibitor preve nted tetanus toroid antigen-specific T cell proliferation and expansion but failed to block activation of Zap70 or p56Lck after anti-CD3 stimulation o f human T cells. Taken together, these findings suggest that AG-490 inhibit s the JAK3-mediated Type II signaling pathway but not the T cell receptor-d erived Type I pathway and possesses therapeutic potential for T cell-derive d pathologies such as graft-versus-host disease, allergy, and autoimmune di sorders.