title: Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma.
abstract: Severe asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high-dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the Janus kinase-signal transducers and activators of transcription pathway. We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, quantitative PCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating interleukin (IL)-13 signalling in vitroSOCS1 gene expression was significantly lower in the airways of severe asthmatics compared with mild/moderate asthmatics, and was inversely associated with airway eosinophilia and other measures of T-helper type 2 (Th2) inflammation. Immunohistochemistry demonstrated SOCS1 was predominantly localised to the bronchial epithelium. SOCS1 overexpression inhibited IL-13-mediated chemokine ligand (CCL) 26 (eotaxin-3) mRNA expression in bronchial epithelial cells.Severe asthma patients with persistent airway eosinophilia and Th2 inflammation have reduced airway epithelial SOCS1 expression. SOCS1 inhibits epithelial IL-13 signalling, supporting its key role in regulating Th2-driven eosinophilia in severe asthma.
authors.affiliation: Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Belfast, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Doran
authors.affiliation: ITGR Diagnostic Discovery, Genentech, San Francisco, CA, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Choy
authors.affiliation: Department of Infection, Immunity and Inflammation, Maurice Shock Medical Sciences Building, Leicester, UK.
authors.forename: Aarti
authors.initials: A
authors.lastname: Shikotra
authors.affiliation: Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Belfast, UK.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Butler
authors.affiliation: Histopathology and Cytopathology Laboratory, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Declan M
authors.initials: DM
authors.lastname: O'Rourke
authors.affiliation: Inflammation, Amgen Inc, Thousand Oaks, CA, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Johnston
authors.affiliation: Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Belfast, UK.
authors.forename: Adrien
authors.initials: A
authors.lastname: Kissenpfennig
authors.affiliation: Department of Infection, Immunity and Inflammation, Maurice Shock Medical Sciences Building, Leicester, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
authors.affiliation: ITGR Diagnostic Discovery, Genentech, San Francisco, CA, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
authors.affiliation: Centre for Infection and Immunity, Health Sciences Building, Queens University Belfast, Belfast, UK l.heaney@qub.ac.uk.
authors.forename: Liam G
authors.initials: LG
authors.lastname: Heaney
mesh_terms: D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism*; D001706:Biopsy; D001980:Bronchi / Q000378:metabolism; D001999:Bronchoscopy; D016022:Case-Control Studies; D002460:Cell Line; D000075906:Chemokine CCL26 / Q000378:metabolism; D015331:Cohort Studies; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011657:Pulmonary Eosinophilia / Q000188:drug therapy / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology; D055815:Young Adult
chemical_list: C120429:CCL26 protein, human; D000075906:Chemokine CCL26; D018793:Interleukin-13; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins