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Immunology Program, Cell Therapeutics, Inc., Seattle, WA 98119
We have previously shown that lisofylline (LSF) inhibits murine
Th1-mediated disease in vivo by blocking IL-12-induced differentiation
of Th1 cells. The cellular and molecular mechanisms underlying this
inhibition were further explored by testing LSF in several
IL-12-responsive model systems in vitro. IL-12-dependent Th1
differentiation was abrogated by LSF and yielded effector T cells that
were deficient in proinflammatory cytokine secretion, including
IFN-
, IL-2, and TNF-
. The diminished Th1 phenotype resulted from
both a lower frequency of IL-12-derived Th1 clones and a reduced
capacity of individual clones to secrete IFN- due to lower levels of
IFN- mRNA. The arrest in Th1 development resulted from a blockade of
IL-12 signaling that preceded the Th0 to Th1 transition. Thus, LSF
blocked IL-12-enhanced IFN- production in anti-CD3-stimulated T
cells and prevented IL-12-mediated repression of the transcription
factor GATA-3. Lisofylline also inhibited IL-12-induced
increases in STAT4 tyrosine phosphorylation, but did not block TCR
signaling or inhibit acquisition of IL-12 responsiveness. These
findings were extended to show that LSF also inhibits IL-12-dependent
responses in human T cells. LSF, which has one asymmetric chiral
center, was selectively inhibitory for IL-12 signaling compared with
its S-enantiomer (1501-S) and the oxidized side chain
analog, pentoxifylline. The results suggest that LSF may be useful as a
modulator of Th1-mediated disease in humans.
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