Min Xie1, Anthony T Mustovich2, Yi Jiang2, John B Trudeau2, Anuradha Ray2, Prabir Ray2, Haizhen Hu2, Fernando Holguin2, Bruce Freeman2, Sally E Wenzel3. 1. Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa. 2. University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa. 3. University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa. Electronic address: wenzelse@upmc.edu.
Abstract
BACKGROUND: Severe asthma (SA) can involve both innate and type 2 cytokine-associated adaptive immunity. Although IL-27 has been reported to potentiate TH1 responses (including the chemokine CXCL9) and suppress TH2 responses, its function in asthmatic patients is unknown. OBJECTIVE: We sought to evaluate IL-27 expression in human asthma alone and in combination with type 2 immunity to determine the relationship to disease severity and CXCL9 expression. We also sought to model these interactions in vitro in human bronchial epithelial cells. METHODS: Bronchoalveolar lavage cells from 87 participants were evaluated for IL-27 mRNA and protein alone and in association with epithelial CCL26 (a marker of type 2 activation) in relation to asthma severity and CXCL9 mRNA. Human bronchial epithelial cells cultured at the air-liquid interface and stimulated with IL-27 (1-100 ng/mL) with or without IL-13 (1 ng/mL) were evaluated for CXCL9 expression by using quantitative real-time PCR and ELISA. Phosphorylated and total signal transducer and activator of transcription (STAT) 1/3 were detected by means of Western blotting. Small interfering RNA knockdown of STAT1 or STAT3 was performed. RESULTS: Bronchoalveolar lavage cell IL-27 mRNA and protein levels were increased in asthmatic patients. Patients with evidence for type 2 pathway activation had higher IL-27 expression (P = .02). Combined IL-27 and CCL26 expression associated with more SA and higher CXCL9 expression (P = .004 and P = .007 respectively), whereas IL-27 alone was associated with milder disease. In vitro IL-13 augmented IL-27-induced CXCL9 expression, which appeared to be due to augmented STAT1 activation and reduced STAT3 activation. CONCLUSIONS: IL-27, in combination with a type 2/CCL26 signature, identifies a more SA phenotype, perhaps through combined effects of IL-27 and IL-13 on STAT signaling. Understanding these interactions could lead to new targets for asthma therapy.
BACKGROUND: Severe asthma (SA) can involve both innate and type 2 cytokine-associated adaptive immunity. Although IL-27 has been reported to potentiate TH1 responses (including the chemokine CXCL9) and suppress TH2 responses, its function in asthmatic patients is unknown. OBJECTIVE: We sought to evaluate IL-27 expression in humanasthma alone and in combination with type 2 immunity to determine the relationship to disease severity and CXCL9 expression. We also sought to model these interactions in vitro in human bronchial epithelial cells. METHODS: Bronchoalveolar lavage cells from 87 participants were evaluated for IL-27 mRNA and protein alone and in association with epithelial CCL26 (a marker of type 2 activation) in relation to asthma severity and CXCL9 mRNA. Human bronchial epithelial cells cultured at the air-liquid interface and stimulated with IL-27 (1-100 ng/mL) with or without IL-13 (1 ng/mL) were evaluated for CXCL9 expression by using quantitative real-time PCR and ELISA. Phosphorylated and total signal transducer and activator of transcription (STAT) 1/3 were detected by means of Western blotting. Small interfering RNA knockdown of STAT1 or STAT3 was performed. RESULTS: Bronchoalveolar lavage cell IL-27 mRNA and protein levels were increased in asthmatic patients. Patients with evidence for type 2 pathway activation had higher IL-27 expression (P = .02). Combined IL-27 and CCL26 expression associated with more SA and higher CXCL9 expression (P = .004 and P = .007 respectively), whereas IL-27 alone was associated with milder disease. In vitro IL-13 augmented IL-27-induced CXCL9 expression, which appeared to be due to augmented STAT1 activation and reduced STAT3 activation. CONCLUSIONS:IL-27, in combination with a type 2/CCL26 signature, identifies a more SA phenotype, perhaps through combined effects of IL-27 and IL-13 on STAT signaling. Understanding these interactions could lead to new targets for asthma therapy.
Keywords:
Asthma; CXCL9; IL-13; IL-27; epithelial cells; signal transducer and activator of transcription 1; signal transducer and activator of transcription 3
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