論文 - 詳細
| RRC ID | 42355 |
|---|---|
| 著者 | Linwong W, Hirasawa N, Aoyama S, Hamada H, Saito T, Ohuchi K. |
| タイトル | Inhibition of the antigen-induced activation of rodent mast cells by putative Janus kinase 3 inhibitors WHI-P131 and WHI-P154 in a Janus kinase 3-independent manner. |
| ジャーナル | Br J Pharmacol |
| Abstract |
We analyzed the effects of the Janus kinase 3 (Jak3)-specific inhibitor WHI-P131 (4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline) and the Jak3/Syk inhibitor WHI-P154 (4-(3'-bromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline) on the antigen-induced activation of mast cells. In the rat mast cell line RBL-2H3, both WHI-P131 and WHI-P154 inhibited the antigen-induced degranulation and phosphorylation of p44/42 mitogen-activated protein kinase (MAPK), p38 MAPK and c-Jun N-terminal kinase (JNK). The phosphorylation of Gab2, Akt and Vav was also inhibited by WHI-P131 and WHI-P154, indicating that these inhibitors suppress the activation of phosphatidylinositol 3-kinase (PI3K). In bone marrow-derived mast cells (BMMCs) from Jak3-deficient (Jak3-/-) mice, degranulation and activation of MAPKs were induced by the antigen in almost the same extent as in BMMCs from wild-type mice. In addition, the antigen-induced degranulation and activation of MAPKs were inhibited by WHI-P131 and WHI-P154 in both groups of BMMCs, indicating that these compounds inhibit a certain step except for Jak3. The antigen-induced increase in the activity of Fyn, a probable tyrosine kinase of Gab2, was also inhibited by WHI-P131 and WHI-P154 in RBL-2H3 cells. In BMMCs from Jak3-/- mice, the antigen stimulation induced tyrosine phosphorylation of Fyn, which was inhibited by WHI-P131, as well as in BMMCs from wild-type mice and in RBL-2H3 cells. These findings suggest that Jak3 does not play a significant role in the antigen-induced degranulation and phosphorylation of MAPKs, and that WHI-P131 and WHI-P154 inhibit the PI3K pathway by preventing the antigen-induced activation of Fyn, thus inhibiting the antigen-induced degranulation and phosphorylation of MAPKs in mast cells. |
| 巻・号 | 145(6) |
| ページ | 818-28 |
| 公開日 | 2005-7-1 |
| DOI | 10.1038/sj.bjp.0706240 |
| PII | 0706240 |
| PMID | 15852029 |
| PMC | PMC1576194 |
| MeSH | Adaptor Proteins, Signal Transducing Animals Cell Cycle Proteins / metabolism Cell Degranulation / drug effects Cell Line, Tumor Dinitrophenols / pharmacology Hexosaminidases / metabolism Immunoglobulin E / pharmacology Janus Kinase 3 Mast Cells / drug effects* Mast Cells / enzymology Mast Cells / immunology Mast Cells / metabolism Mice Mice, Knockout Mitogen-Activated Protein Kinases / metabolism Phosphatidylinositol 3-Kinases / metabolism Phosphoproteins / metabolism Phosphorylation / drug effects Protein Serine-Threonine Kinases / metabolism Protein-Tyrosine Kinases / antagonists & inhibitors* Protein-Tyrosine Kinases / deficiency Protein-Tyrosine Kinases / genetics Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-fyn Proto-Oncogene Proteins c-vav Quinazolines / pharmacology* Rats Serum Albumin / pharmacology src-Family Kinases / metabolism |
| IF | 7.73 |
| 引用数 | 12 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | |