Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells.
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 alpha activation of NF-kappaB 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. (Blood. 2000;95:3816-3822)
Wang
L H
LH
Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute, Frederick, MD 21702, USA.
Kirken
R A
RA
Yang
X Y
XY
Erwin
R A
RA
DaSilva
L
L
Yu
C R
CR
Farrar
W L
WL
D000818:Animals; D017252:CD3 Complex / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000494:pharmacology*; D053616:Janus Kinase 3; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D018123:Receptors, Interleukin / Q000096:biosynthesis*; D050800:STAT6 Transcription Factor; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology*
D017252:CD3 Complex; D016207:Cytokines; D004791:Enzyme Inhibitors; D018123:Receptors, Interleukin; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3