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

Kyoko Niimi, Koichiro Asano, 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, Akitoshi Ishizaka

Research output: Contribution to journalArticle

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Abstract

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 low 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.

Original languageEnglish
Pages (from-to)489-495
Number of pages7
JournalJournal of Immunology
Volume178
Issue number1
Publication statusPublished - 2007 Jan 1

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Chemokine CCL11
Poly I
Double-Stranded RNA
Smooth Muscle Myocytes
RNA Viruses
Chemokines
Interleukin-4
RNA Virus Infections
Toll-Like Receptor 3
Inflammation
Rhinovirus
Chemokine CCL5
Respiratory Syncytial Viruses
Virus Replication
Fluorescein
Eosinophils
Confocal Microscopy
Respiratory Tract Infections
Small Interfering RNA
Transfection

ASJC Scopus subject areas

  • Immunology

Cite this

Niimi, K., Asano, K., Shiraishi, Y., Nakajima, T., Wakaki, M., Kagyo, J., ... Ishizaka, A. (2007). TLR3-mediated synthesis and release of Eotaxin-1/CCL11 from human bronchial smooth muscle cells stimulated with double-stranded RNA. Journal of Immunology, 178(1), 489-495.

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

In: Journal of Immunology, Vol. 178, No. 1, 01.01.2007, p. 489-495.

Research output: Contribution to journalArticle

Niimi, K, Asano, K, Shiraishi, Y, Nakajima, T, Wakaki, M, Kagyo, J, Takihara, T, Suzuki, Y, Fukunaga, K, Shiomi, T, Oguma, T, Sayama, K, Yamaguchi, K, Natori, Y, Matsumoto, M, Seya, T, Yamaya, M & Ishizaka, A 2007, 'TLR3-mediated synthesis and release of Eotaxin-1/CCL11 from human bronchial smooth muscle cells stimulated with double-stranded RNA', Journal of Immunology, vol. 178, no. 1, pp. 489-495.
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. / TLR3-mediated synthesis and release of Eotaxin-1/CCL11 from human bronchial smooth muscle cells stimulated with double-stranded RNA. In: Journal of Immunology. 2007 ; Vol. 178, No. 1. pp. 489-495.
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AU - Nakajima, Takeshi

AU - Wakaki, Misa

AU - Kagyo, Junko

AU - Takihara, Takahisa

AU - Suzuki, Yusuke

AU - Fukunaga, Koichi

AU - Shiomi, Tetsuya

AU - Oguma, Tsuyoshi

AU - Sayama, Koichi

AU - Yamaguchi, Kazuhiro

AU - Natori, Yukikazu

AU - Matsumoto, Misako

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N2 - 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 low 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.

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