Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells

J Leukoc Biol. 1999 Jun;65(6):891-9. doi: 10.1002/jlb.65.6.891.


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.

MeSH terms

  • Animals
  • Antigens / physiology
  • Cell Division / drug effects
  • Cytokines / pharmacology*
  • DNA-Binding Proteins / antagonists & inhibitors
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Interleukin-2 / antagonists & inhibitors
  • Janus Kinase 3
  • Lymphocyte Activation / immunology
  • Mice
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Protein-Tyrosine Kinases / physiology*
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Transcription Factors / physiology*
  • Tyrphostins / pharmacology*


  • Antigens
  • Cytokines
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Interleukin-2
  • Transcription Factors
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Protein-Tyrosine Kinases
  • JAK3 protein, human
  • Jak3 protein, mouse
  • Janus Kinase 3