Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation

Shigeki Matsubara, Toshiyuki Koya, Katsuyuki Takeda, Anthony Joetham, Nobuaki Miyahara, Polly Pine, Esteban S. Masuda, Christina H. Swasey, Erwin W. Gelfand

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

We evaluated the role of Syk, using an inhibitor, on allergen-induced airway hyperresponsiveness (AHR) and airway inflammation in a system shown to be B cell- and mast cell-independent. Sensitization of BALB/c mice with ovalbumin (OVA) and alum after three consecutive OVA challenges resulted in AHR to inhaled methacholine and airway inflammation. The Syk inhibitor R406 (30 mg/kg, administered orally, twice daily) prevented the development of AHR, increases in eosinophils and lymphocytes and IL-13 levels in bronchoalveolar lavage (BAL) fluid, and goblet cell metaplasia when administered after sensitization and before challenge with OVA. Levels of IL-4, IL-5, and IFN-γ in BAL fluid and allergen-specific antibody levels in serum were not affected by treatment. Because many of these responses may be influenced by dendritic cell function, we investigated the effect of R406 on bone marrow-derived dendritic cell (BMDC) function. Co-culture of BMDC with immune complexes of OVA and IgG anti-OVA together with OVA-sensitized spleen mononuclear cells resulted in increases in IL-13 production. IL-13 production was inhibited if the BMDCs were pretreated with the Syk inhibitor. Intratracheal transfer of immune complex-pulsed BMDCs (but not nonpulsed BMDCs) to naive mice before airway allergen challenge induced the development of AHR and increases in BAL eosinophils and lymphocytes. All of these responses were inhibited if the transferred BMDCs were pretreated with R406. These results demonstrate that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.

Original languageEnglish
Pages (from-to)426-433
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume34
Issue number4
DOIs
Publication statusPublished - Apr 2006
Externally publishedYes

Fingerprint

Ovalbumin
Dendritic Cells
Chemical activation
Allergens
Interleukin-13
Inflammation
Bronchoalveolar Lavage Fluid
Antigen-Antibody Complex
Eosinophils
Bone Marrow
Lymphocytes
Goblet Cells
Methacholine Chloride
Interleukin-5
Metaplasia
Bronchoalveolar Lavage
Coculture Techniques
Mast Cells
Interleukin-4
Bone

Keywords

  • AHR
  • Dendritic cells
  • Eosinophils
  • Mice
  • Syk

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Pulmonary and Respiratory Medicine

Cite this

Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation. / Matsubara, Shigeki; Koya, Toshiyuki; Takeda, Katsuyuki; Joetham, Anthony; Miyahara, Nobuaki; Pine, Polly; Masuda, Esteban S.; Swasey, Christina H.; Gelfand, Erwin W.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 34, No. 4, 04.2006, p. 426-433.

Research output: Contribution to journalArticle

Matsubara, Shigeki ; Koya, Toshiyuki ; Takeda, Katsuyuki ; Joetham, Anthony ; Miyahara, Nobuaki ; Pine, Polly ; Masuda, Esteban S. ; Swasey, Christina H. ; Gelfand, Erwin W. / Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation. In: American Journal of Respiratory Cell and Molecular Biology. 2006 ; Vol. 34, No. 4. pp. 426-433.
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