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

• Published in: European journal of pharmacology 2008-08, Vol.590 (1), p.409-416
• Main Authors: Ohga, Keiko, Kuromitsu, Sadao, Takezawa, Ryuichi, Numazaki, Mako, Ishikawa, Jun, Nagashima, Shinya, Shimizu, Yasuaki
• Format: Article
• Language: English
• Subjects: Animals; Asthma; Asthma - drug therapy; Asthma - immunology; Biological and medical sciences; Bronchial Hyperreactivity - drug therapy; Cell Differentiation - drug effects; Chronic obstructive pulmonary disease, asthma; Dose-Response Relationship, Drug; Eosinophilia - drug therapy; Female; GATA-3; GATA3 Transcription Factor - genetics; IL-4 (Interleukin-4); Interferon-gamma - biosynthesis; Interleukin-4 - antagonists & inhibitors; Interleukin-4 - biosynthesis; Male; Medical sciences; Mice; Mice, Inbred C57BL; Morpholines - pharmacology; Morpholines - therapeutic use; Pharmacology. Drug treatments; Pneumology; Promoter Regions, Genetic; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Rats, Inbred BN; Rats, Wistar; Spleen - cytology; STAT6 (signal transducer and activator of transcription) 6; STAT6 Transcription Factor - genetics; T-Lymphocytes - cytology; Th (T helper) 2 cell; Th2 Cells - cytology; YM-341619
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2008.06.035

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-γ 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-γ 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.