Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3816-3822
Selective disruption of interleukin 4 autocrine-regulated loop by
a tyrosine kinase inhibitor restricts activity of T-helper 2 cells
Li Hua Wang,
Robert A. Kirken,
Xiao Yi Yang,
Rebecca A. Erwin,
Luis DaSilva,
Cheng-Rong Yu, and
William L. Farrar
From the Cytokine Molecular Mechanisms Section, Laboratory of
Molecular Immunoregulation, Division of Basic Sciences; the Intramural
Research Support Program, SAIC Frederick; the Laboratory of
Experimental Immunology; National Cancer Institute-Frederick Cancer
Research and Development Center, Frederick, MD; and the Department of
Integrative Biology and Pharmacology, University of Texas at Houston,
Houston, TX.
Interleukin (IL) 4 is a potent immunomodulatory cytokine secreted by
T-helper 2 (Th2) cells and Th2 mast cells that promotes the commitment
of cells. However, unregulated production and release of IL-4 can
exacerbate allergic reactions and increase susceptibility to infectious
organisms and viruses. Here, we present evidence that AG-490, a Janus
tyrosine kinase (JAK) 2-JAK3 inhibitor, effectively blocked IL-4 gene
expression and secretion in the Th2 cell line D10 that was not
occurring after anti-CD3 antibody stimulation, whereas AG-490 had no
inhibitory effect on production of other Th2 cytokines or cytokines
synthesized by the corresponding Th1 cell line clone 29. AG-490
potently inhibited IL-4-mediated proliferation of both D10 and the
IL-4-dependent cell line CT.4S. Moreover, AG-490 markedly inhibited
IL-4 activation of JAK3 and blocked the downstream activation of signal
transducer and activator of transcription 6, as judged by tyrosine
phosphorylation, DNA binding, and transcription assays. In contrast,
AG-490 did not affect tumor necrosis factor 
activation of NF-
B
at similar concentrations of drug. These data suggest that tyrosine
kinase inhibitors that inhibit JAK3 may have previously unrecognized
and selective clinical potential as immunotherapeutic drugs to treat
Th2-mediated diseases driven by IL-4.
