YM-341619 suppresses the differentiation of spleen T cells into Th2 cells in vitro, eosinophilia, and airway hyperresponsiveness in rat allergic models.

Abstract

T helper (Th) 2 cells play a central role in the pathogenesis of allergic diseases such as allergic asthma, atopic dermatitis, and allergic rhinitis. We have found that YM-341619 hydrochloride, which suppressed IL-4-induced STAT6-dependent reporter gene expression, inhibited the differentiation of mouse spleen T cells into Th2 cells in vitro. YM-341619 suppressed the production of IL-4 and the expression of GATA-3 mRNA, a Th2 transcription factor, in T cells cultured with anti-CD3 antibody and anti-CD28 antibody in the presence of IL-4. In contrast, the production of IFN-gamma and the expression of T-bet mRNA, a Th1 transcription factor, in T cells cultured with anti-CD3 antibody in the presence of IL-12, were not effected by YM-341619. Orally administered YM-341619 (0.003-0.03 mg/kg) reduced the plasma IgE level of DNP-Ascaris-sensitized rats, but not the IgG(2a) level. YM-341619 suppressed IL-4 and IL-13 production in the splenocytes of these DNP-Ascaris-sensitized rats without augmenting IFN-gamma production. YM-341619 also dose-dependently suppressed eosinophil accumulation in the lung (0.003-3 mg/kg, p.o.) and airway hyperresponsiveness (0.3-3 mg/kg, p.o.) induced by repeated exposure to ovalbumin in ovalbumin-sensitized rats. These results suggest that YM-341619 has the ability to suppress allergen-induced Th2 responses by selectively inhibiting the differentiation of CD4(+) T cells into the Th2 subset.

• Authors: Keiko Ohga, Sadao Kuromitsu, Ryuichi Takezawa, Mako Numazaki, Jun Ishikawa, Shinya Nagashima, Yasuaki Shimizu
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 590 Issue 1-3 Pg. 409-16 (Aug 20 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 18590722 (Publication Type: Journal Article)

Chemical References

• 2-((4-morpholin-4-ylphenyl)amino)-4-((2,3,6-trifluorobenzyl)amino)pyrimidine-5-carboxamide
• GATA3 Transcription Factor
• Morpholines
• Pyrimidines
• STAT6 Transcription Factor
• Interleukin-4
• Interferon-gamma

Topics

• Animals
• Asthma (drug therapy, immunology)
• Bronchial Hyperreactivity (drug therapy)
• Cell Differentiation (drug effects)
• Dose-Response Relationship, Drug
• Eosinophilia (drug therapy)
• Female
• GATA3 Transcription Factor (genetics)
• Interferon-gamma (biosynthesis)
• Interleukin-4 (antagonists & inhibitors, biosynthesis)
• Male
• Mice
• Mice, Inbred C57BL
• Morpholines (pharmacology, therapeutic use)
• Promoter Regions, Genetic
• Pyrimidines (pharmacology, therapeutic use)
• Rats
• Rats, Inbred BN
• Rats, Wistar
• STAT6 Transcription Factor (genetics)
• Spleen (cytology)
• T-Lymphocytes (cytology)
• Th2 Cells (cytology)