TLR3-mediated synthesis and release of Eotaxin-1/CCL11 from human bronchial smooth muscle cells stimulated with double-stranded RNA

被引:42
作者
Niimi, Kyoko
Asano, Koichiro
Shiraishi, Yoshiki
Nakajima, Takeshi
Wakaki, Misa
Kagyo, Junko
Takihara, Takahisa
Suzuki, Yusuke
Fukunaga, Koichi
Shiomi, Tetsuya
Oguma, Tsuyoshi
Sayama, Koichi
Yamaguchi, Kazuhiro
Natori, Yukikazu
Matsumoto, Misako
Seya, Tsukasa
Yamaya, Mutsuo
Ishizaka, Akitoshi
机构
[1] Keio Univ, Sch Med, Div Pulm Med, Dept Med,Shinjuku Ku, Tokyo 1608582, Japan
[2] Keio Univ, Keio Pfizer Res Labs, Tokyo 1608582, Japan
[3] RNAi, Tokyo, Japan
[4] Hokkaido Univ, Dept Microbiol & Immunol, Grad Sch Med, Sapporo, Hokkaido 060, Japan
[5] Tohoku Univ, Sch Med, Dept Geriatr & Gerontol, Sendai, Miyagi 980, Japan
关键词
D O I
10.4049/jimmunol.178.1.489
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Respiratory infections with RNA viruses, such as rhinovirus or respiratory syncytial virus, are a major cause of asthma exacerbation, accompanied by enhanced neutrophilic and/or eosinophilic inflammation of the airways. We studied the effects of dsRNA synthesized during RNA virus replication, and of its receptor, TLR3, on the synthesis of eosinophilic chemokines in bronchial smooth muscle cells (BSMC). Synthetic dsRNA, polyinosinic-cystidic acid (poly(I:C)), induced the synthesis of eosinophilic chemokines, eotaxin-1/CCL11 and RANTES/CCL5, from primary cultures of human BSMC, and IL-4 increased synergistically the synthesis of poly(I:C)-induced CCL11. A robust eosinophil chemotactic activity was released from BSMC stimulated with poly(I:C) and IL-4, which was mostly inhibited by preincubation with an anti-CCL11, but not with an anti-CCL5 Ab. Although the inummoreactivity of TLR3 was detectable on the cellular surface of BSMC by flow cytometric analysis, pretreatment with an anti-TLR3-neutralizing Ab failed to block the poly(I:C)-induced synthesis of CCL11. We have determined by confocal laser-scanning microscopy that the inummoreactivity of TLR3 was aggregated intracellularly in poly(I:C)-stimulated BSMC, colocalizing with fluorescein-labeled poly(I:C). The synthesis of CCL11 was prominently inhibited by the transfection of TLR3-specific small interfering RNA or by bafilomycin A1, an endosomal acidification inhibitor, further supporting the essential role played by intracellular TLR3 in the synthesis of poly(I:C)-induced CCL11 in BSMC. In conclusion, these observations suggest that, by activating intracellular TLR3 in BSMC, respiratory RNA virus infections stimulate the production of CCL11 and enhance eosinophilic inflammation of the airways in the Th2-dominant microenvironment.
引用
收藏
页码:489 / 495
页数:7
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