Cyclooxygenase-2/prostaglandin D2/CRTH2 pathway mediates double-stranded RNA-induced enhancement of allergic airway inflammation

Yoshiki Shiraishi, Koichiro Asano, Kyoko Niimi, Koichi Fukunaga, Misa Wakaki, Junko Kagyo, Takahisa Takihara, Soichiro Ueda, Takeshi Nakajima, Tsuyoshi Oguma, Yusuke Suzuki, Tetsuya Shiomi, Koichi Sayama, Shizuko Kagawa, Eiji Ikeda, Hiroyuki Hirai, Kinya Nagata, Masataka Nakamura, Taku Miyasho, Akitoshi Ishizaka

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67 Citations (Scopus)

Abstract

Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD 2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness.

Original languageEnglish
Pages (from-to)541-549
Number of pages9
JournalJournal of Immunology
Volume180
Issue number1
DOIs
Publication statusPublished - 2008 Jan 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Shiraishi, Y., Asano, K., Niimi, K., Fukunaga, K., Wakaki, M., Kagyo, J., Takihara, T., Ueda, S., Nakajima, T., Oguma, T., Suzuki, Y., Shiomi, T., Sayama, K., Kagawa, S., Ikeda, E., Hirai, H., Nagata, K., Nakamura, M., Miyasho, T., & Ishizaka, A. (2008). Cyclooxygenase-2/prostaglandin D2/CRTH2 pathway mediates double-stranded RNA-induced enhancement of allergic airway inflammation. Journal of Immunology, 180(1), 541-549. https://doi.org/10.4049/jimmunol.180.1.541