title: Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function.
abstract: 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)4-deficient 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-cell-deficient 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-kappaB 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 TLR4-mediated induction of GATA1 and subsequent increase in Th2 cytokine production.
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Yukiko I
authors.initials: YI
authors.lastname: Nigo
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yamashita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hirahara
authors.forename: Ryo
authors.initials: R
authors.lastname: Shinnakasu
authors.forename: Masamichi
authors.initials: M
authors.lastname: Inami
authors.forename: Motoko
authors.initials: M
authors.lastname: Kimura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kohno
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D050982:GATA1 Transcription Factor / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; C494689:Gata1 protein, mouse; C494712:Gata2 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4