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

Robert A. Kirken, Rebecca A. Erwin, Dennis Taub, William J Murphy, Fariba Behbod, Lihua Wang, Federica Pericle, William L. Farrar

Research output: Contribution to journalArticle

101 Scopus citations

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 languageEnglish (US)
Pages (from-to)891-899
Number of pages9
JournalJournal of Leukocyte Biology
Volume65
Issue number6
StatePublished - 1999
Externally publishedYes

Keywords

  • Interleukin-2
  • Kinase inhibitors
  • Stats
  • YAKs

ASJC Scopus subject areas

  • Cell Biology

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