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TLR3-Mediated Synthesis and Release of Eotaxin-1/CCL11 from Human Bronchial Smooth Muscle Cells Stimulated with Double-Stranded RNA¹

Kyoko Niimi^*,, Koichiro Asano^2,*,, Yoshiki Shiraishi^*,, Takeshi Nakajima^*,, Misa Wakaki^*,, Junko Kagyo^*,, Takahisa Takihara^*,, Yusuke Suzuki^*, Koichi Fukunaga^*, Tetsuya Shiomi^*, Tsuyoshi Oguma^*, Koichi Sayama^*, Kazuhiro Yamaguchi^*, Yukikazu Natori, Misako Matsumoto, Tsukasa Seya, Mutsuo Yamaya^¶ and Akitoshi Ishizaka^*,

^* Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; Keio-Pfizer Research Laboratories, Shinanomachi Campus Research Park, Keio University School of Medicine, Tokyo, Japan; RNAi, Tokyo, Japan; Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; and ^¶ Department of Geriatrics and Gerontology, Tohoku University School of Medicine, Sendai, Japan

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 immunoreactivity 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 immunoreactivity 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology.

² Address correspondence and reprint requests to Dr. Koichiro Asano, Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail address: ko-asano{at}qa2.so-net.ne.jp

³ Abbreviations used in this paper: RSV, respiratory syncytial virus; BSMC, bronchial smooth muscle cell; EEA-1, early endosome Ag 1; poly(I:C), polyinosinic-cystidic acid; siRNA, small interfering RNA.

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