Selective pharmacologic inhibition of murine and human IL-12-dependent Th1 differentiation and IL-12 signaling.
J Immunol
; 163(12): 6567-74, 1999 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-10586050
ABSTRACT
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-gamma, IL-2, and TNF-alpha. 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-gamma due to lower levels of IFN-gamma 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-gamma 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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pentoxifilina
/
Transdução de Sinais
/
Células Th1
/
Interleucina-12
/
Imunossupressores
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Immunol
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
Estados Unidos