title: IL-27 and type 2 immunity in asthmatic patients: association with severity, CXCL9, and signal transducer and activator of transcription signaling.
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.
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Mustovich
authors.affiliation: University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: John B
authors.initials: JB
authors.lastname: Trudeau
authors.affiliation: University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
authors.affiliation: University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
authors.affiliation: University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Hu
authors.affiliation: University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Fernando
authors.initials: F
authors.lastname: Holguin
authors.affiliation: University of Pittsburgh Asthma Institute@UPMC, Pulmonary Allergy Critical Care Medicine Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Bruce
authors.initials: B
authors.lastname: Freeman
authors.affiliation: 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.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D000075906:Chemokine CCL26; D054370:Chemokine CXCL9 / Q000378:metabolism; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005541:Forced Expiratory Volume; D015870:Gene Expression; D006801:Humans; D007109:Immunity; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D064094:Interleukin-27 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D015415:Biomarkers; C120429:CCL26 protein, human; D000075906:Chemokine CCL26; D054370:Chemokine CXCL9; D019742:Chemokines, CC; D016207:Cytokines; D064094:Interleukin-27; D050791:STAT Transcription Factors; D009569:Nitric Oxide; D007073:Immunoglobulin E
keywords: Asthma; CXCL9; IL-13; IL-27; epithelial cells; signal transducer and activator of transcription 1; signal transducer and activator of transcription 3