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Am J Respir Cell Mol Biol ; 43(5): 520-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19933379

RESUMO

We previously reported that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c(high)CD8α(high)CD11b(low) dendritic cells and CD4(+)CD25(+)ICOS(+)Foxp3(+)IL-10(+) T-regulatory cells in the lung of allergen-sensitized and -challenged mice. In this study, we evaluated the effect of Flt3-L on Th17 cells and expression of suppressors of cytokine signaling (SOCS) proteins in the lungs of house dust mite (HDM)-sensitized and -challenged mice. BALB/c mice were sensitized and challenged with HDM, and AHR to methacholine was established. Mice were treated with Flt3-L (5 µg, intraperitoneal) daily for 10 days. Levels of IL-4, -5, -6, -8, and -13, and transforming growth factor (TGF)-ß in the bronchoalveolar lavage fluid (BALF) were examined by ELISA. Flt3-L treatment reversed existing AHR to methacholine and substantially decreased eosinophils, neutrophils, IL-5, -6, -8, and IL-13, and TGF-ß levels in the BALF. HDM-sensitized and -challenged mice showed a significant increase in lung CD4(+)IL-17(+)IL-23R(+)CD25⁻ T cells with high expression of retinoic acid-related orphan receptor (ROR)-γt transcripts. However, administration of Flt3-L substantially decreased the number of lung CD4(+)IL-17(+)IL-23R(+)CD25⁻ T cells, with significantly decreased expression of ROR-γt mRNA in these cells. HDM sensitization caused a significant increase in the expression of SOCS-1, -3, and -5 in the lung. Flt3-L treatment abolished the increase in SOCS-1 and SOCS-3 proteins, whereas SOCS-5 expression was significantly reduced. These data suggest that the therapeutic effect of Flt3-L in reversing the hallmarks of allergic asthma in a mouse model is mediated by decreasing IL-6 and TGF-ß levels in the BALF, which, in turn, decrease CD4(+)IL-17(+)IL-23R(+)ROR-γt(+)CD25⁻ T cells and the expression of SOCS-1 and SOCS-3 in the lung of HDM-sensitized and -challenged mice.


Assuntos
Imunização , Pulmão/imunologia , Pulmão/parasitologia , Proteínas de Membrana/farmacologia , Pyroglyphidae/imunologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Líquido da Lavagem Broncoalveolar/citologia , Antígenos CD4/metabolismo , Contagem de Células , Separação Celular , Citocinas/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Pyroglyphidae/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Interleucina/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Células Th2/imunologia
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