Regulation of Allergic Airway Inflammation through Toll-Like Receptor 4-Mediated Modification of Mast Cell Function

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-02, Vol.103 (7), p.2286-2291
• Main Authors: Nigo, Yukiko I., Yamashita, Masakatsu, Hirahara, Kiyoshi, Shinnakasu, Ryo, Inami, Masamichi, Kimura, Motoko, Hasegawa, Akihiro, Kohno, Yoichi, Nakayama, Toshinori
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Allergies; Animals; Asthma; Asthma - immunology; Biological Sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - immunology; Cells; Cytokines; Cytokines - biosynthesis; Cytokines - genetics; Disease Models, Animal; Eosinophils; GATA1 Transcription Factor - metabolism; GATA2 Transcription Factor - metabolism; Gene expression; Inflammation; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Lungs; Lymphocytes; Mast cells; Mast Cells - drug effects; Mast Cells - immunology; Mast Cells - metabolism; Mice; Mice, Knockout; Neurons; Neutrophils; NF-kappa B - metabolism; Ova; Pulmonary Eosinophilia - immunology; Respiratory Hypersensitivity - immunology; Rodents; Small interfering RNA; Th2 Cells - immunology; Th2 Cells - metabolism; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Transcription, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0510685103

In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by the administration of LPS in wild-type mice, whereas such increase was not observed in mast-cell-deficient mice or Toll-like receptor (TLR)4deficient mice. Adoptive transfer of bone-marrow-derived mast cells (BMMCs) from wild-type, but not from TLR4-deficient, mice restored the increased eosinophilic inflammation in mast-celldeficient mice. Wild-type BMMCs pretreated with LPS in vitro also reconstituted the eosinophilic inflammation. Moreover, in vitro analysis revealed that the treatment of BMMCs with LPS resulted in NF-κB activation, sustained up-regulation of GATA1 and -2 expression, and increased the capability to produce IL-5 and -13. Dramatic increases in the expression of IL-5 and -13 and Eotaxin 2 were detected in LPS-treated BMMCs after costimulation with LPS and IgE/Ag. Overexpression of GATA1, but not GATA2, in MC9 mast cells resulted in increased transcriptional activity of IL-4, -5, and -13. Furthermore, the levels of transcription of Th2 cytokines in BMMCs were decreased by the introduction of small interfering RNA for GATA1. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4mediated induction of GATA1 and subsequent increase in Th2 cytokine production.