Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation.
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-gamma 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.
Matsubara
Shigeki
S
Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO, 80206, USA.
Koya
Toshiyuki
T
Takeda
Katsuyuki
K
Joetham
Anthony
A
Miyahara
Nobuaki
N
Pine
Polly
P
Masuda
Esteban S
ES
Swasey
Christina H
CH
Gelfand
Erwin W
EW
D000485:Allergens; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000201:enzymology* / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D020397:Goblet Cells / Q000473:pathology; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018793:Interleukin-13 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008407:Mast Cells / Q000502:physiology; D008679:Metaplasia; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D010078:Oxazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D000072377:Syk Kinase
D000485:Allergens; D016207:Cytokines; D018793:Interleukin-13; D047908:Intracellular Signaling Peptides and Proteins; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; D016210:Methacholine Chloride; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse