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1.
Clin Sci (Lond) ; 131(20): 2533-2548, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29026003

RESUMO

T helper (Th)17 immune response participates in allergic lung inflammation and asthma is reduced in the absence of interleukin (IL)-17 in mice. Since IL-17A and IL-17F are induced and bind the shared receptor IL-17RA, we asked whether both IL-17A and IL-17F contribute to house dust mite (HDM) induced asthma. We report that allergic lung inflammation is attenuated in absence of either IL-17A or IL-17F with reduced airway hyperreactivity, eosinophilic inflammation, goblet cell hyperplasia, cytokine and chemokine production as found in absence of IL-17RA. Furthermore, specific antibody neutralization of either IL-17A or IL-17F given during the sensitization phase attenuated allergic lung inflammation and airway hyperreactivity. In vitro activation by HDM of primary dendritic cells revealed a comparable induction of CXCL1 and IL-6 expression and the response to IL-17A and IL-17F relied on IL-17RA signaling via the adaptor protein act1 in fibroblasts. Therefore, HDM-induced allergic respiratory response depends on IL-17RA via act1 signaling and inactivation of either IL-17A or IL-17F is sufficient to attenuate allergic asthma in mice.


Assuntos
Asma/tratamento farmacológico , Interleucina-17/antagonistas & inibidores , Pyroglyphidae/imunologia , Alérgenos/imunologia , Animais , Asma/imunologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Interleucina-17/imunologia , Interleucina-6/imunologia , Pulmão/imunologia , Camundongos Endogâmicos C57BL , Células Th17/imunologia , Células Th2/imunologia
2.
J Crohns Colitis ; 10(12): 1428-1436, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27147452

RESUMO

BACKGROUND AND AIMS: Crohn's disease [CD] is a complex disorder characterised by an inappropriate immune response, impaired barrier function and microbial dysbiosis. Mutations in nucleotide oligomeriation domain 2 [NOD2] are CD risk factors. Increase of intestinal permeability, CD4+ T cell infiltration, and bacterial dysbiosis are also seen in Nod2-knockout [Nod2 KO] mice. However, the specificity and relationship between these Nod2-associated abnormalities remain largely unexplored. METHODS: Wild-type [WT], Nod1-knockout [Nod1 KO] and Nod2 KO mice were analysed in parallel. Microbial composition was defined by 454-pyrosequencing of bacterial 16S rRNA genes. Mucin and antimicrobial peptide expression was assessed by RT-PCR. Cell populations from Peyer's patches were determined by flow cytometry. Ussing chambers were used to measure intestinal permeability and bacterial translocation. Finally, to explore the impact of colonisation with mother's microbiota at birth, analyses were also performed in Nod2 KO and WT mice born from WT surrogate mothers after embryo transfer. RESULTS: Nod2 KO mice exhibited colonic bacterial dysbiosis different from WT and Nod1 KO mice. Altered expression of antimicrobial peptides and mucins in ileum and colon was associated with the microbial composition. Bacterial composition of Nod2 KO and WT mice obtained by embryo transfer was similar to that observed in Nod2 KO mice, arguing for a dominant effect of Nod2 KO-associated dysbiosis. In contrast, increased levels of CD4+ T cells and gut barrier defects across Peyer's patches were specific to Nod2 deficiency and independent of Microbial dysbiosis. CONCLUSIONS: Nod2 deficiency is associated with a specific dominant dysbiosis which does not drive mucosal tissue and immune alterations.


Assuntos
Disbiose/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/deficiência , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Feminino , Microbioma Gastrointestinal/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucinas/metabolismo , Proteína Adaptadora de Sinalização NOD2/fisiologia , Nódulos Linfáticos Agregados/fisiopatologia , RNA Ribossômico 16S/genética , Reação em Cadeia da Polimerase em Tempo Real
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