Xiaojing Liu1,2, Shanqun Li1, Jianjun Jin3, Tao Zhu4, Kan Xu5, Cheng Liu6, Yuzhen Zeng1, Ruolin Mao1, Xiangdong Wang3, Zhihong Chen1. 1. Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, Shanghai, China. 2. Respiratory Division of the Affiliated Hospital of Qingdao University, Qingdao, China. 3. Research Center of Zhongshan Hospital, Fudan University, Shanghai, China. 4. Respiratory Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. 5. Geriatric Department of Zhongshan Hospital, Fudan University, Shanghai, China. 6. Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Abstract
BACKGROUND: Interleukin-27 (IL-27) modulates CD4+ T-cell differentiation and function. The aim of this study is to investigate the effect and molecular mechanisms of IL-27 on the development of asthma. METHODS: IL-27 was intranasally administered in an ovalbumin-induced asthma model, and lung mononuclear cells and different Th cell classes were detected by fluorescence-activated cell sorting. The effect and mechanisms of IL-27 on human bronchial epithelial (HBE) cells were investigated by measuring changes in chemotactic factors, cytokines, transcription factors, and signaling pathways. RESULTS: We found that intranasal administration of IL-27 could attenuate airway inflammation and hyperresponsiveness, upregulate the type 1 T helper (Th1)-T memory (Tm) cells and regulatory T (Treg) cells subgroups of lung tissue lymphocytes, and diminish the levels of type 2 T helper (Th2) cytokines. IL-27 upregulated the expression of C-C motif chemokine ligand 2 (CCL2), CCL3, and CCL4 in HBE cells and promoted the production of chemotactic factors to attract monocyte recruitment. Recruited monocytes secondarily secreted IL-27 to influence HBE cells in a positive feedback cycle. After IL-27 intervention, signal transducer and activator of transcription 1 (STAT1) phosphorylation increased, while STAT4 and STAT6 phosphorylation declined. CONCLUSIONS: Preventative intranasal administration of IL-27 can recruit more IL-27-secreted monocytes to the airway and change the different T-cell classes in lung. The improved Th1 environment helps to alleviate Th2-mediated allergic asthma by repairing the STAT1 pathway but not the STAT4 pathway.
BACKGROUND:Interleukin-27 (IL-27) modulates CD4+ T-cell differentiation and function. The aim of this study is to investigate the effect and molecular mechanisms of IL-27 on the development of asthma. METHODS:IL-27 was intranasally administered in an ovalbumin-induced asthma model, and lung mononuclear cells and different Th cell classes were detected by fluorescence-activated cell sorting. The effect and mechanisms of IL-27 on human bronchial epithelial (HBE) cells were investigated by measuring changes in chemotactic factors, cytokines, transcription factors, and signaling pathways. RESULTS: We found that intranasal administration of IL-27 could attenuate airway inflammation and hyperresponsiveness, upregulate the type 1 T helper (Th1)-T memory (Tm) cells and regulatory T (Treg) cells subgroups of lung tissue lymphocytes, and diminish the levels of type 2 T helper (Th2) cytokines. IL-27 upregulated the expression of C-C motif chemokine ligand 2 (CCL2), CCL3, and CCL4 in HBE cells and promoted the production of chemotactic factors to attract monocyte recruitment. Recruited monocytes secondarily secreted IL-27 to influence HBE cells in a positive feedback cycle. After IL-27 intervention, signal transducer and activator of transcription 1 (STAT1) phosphorylation increased, while STAT4 and STAT6 phosphorylation declined. CONCLUSIONS: Preventative intranasal administration of IL-27 can recruit more IL-27-secreted monocytes to the airway and change the different T-cell classes in lung. The improved Th1 environment helps to alleviate Th2-mediated allergic asthma by repairing the STAT1 pathway but not the STAT4 pathway.
Authors: Maria Xydia; Raheleh Rahbari; Eliana Ruggiero; Iain Macaulay; Maxime Tarabichi; Robert Lohmayer; Stefan Wilkening; Tillmann Michels; Daniel Brown; Sebastiaan Vanuytven; Svetlana Mastitskaya; Sean Laidlaw; Niels Grabe; Maria Pritsch; Raffaele Fronza; Klaus Hexel; Steffen Schmitt; Michael Müller-Steinhardt; Niels Halama; Christoph Domschke; Manfred Schmidt; Christof von Kalle; Florian Schütz; Thierry Voet; Philipp Beckhove Journal: Nat Commun Date: 2021-02-18 Impact factor: 14.919