Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons.

Gielen, Vera; Sykes, Annemarie; Zhu, Jie; Chan, Brian; Macintyre, Jonathan; Regamey, Nicolas; Kieninger, Elisabeth; Gupta, Atul; Shoemark, Amelia; Bossley, Cara; Davies, Jane; Saglani, Sejal; Walker, Patrick; Nicholson, Sandra E; Dalpke, Alexander H; Kon, Onn-Min; Bush, Andrew; Johnston, Sebastian L; Edwards, Michael R (2015). Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons. Journal of allergy and clinical immunology, 136(1), 177-188.e11. Mosby 10.1016/j.jaci.2014.11.039

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BACKGROUND

Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown.

OBJECTIVE

We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients.

METHODS

We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes.

RESULTS

We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients.

CONCLUSION

We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Pneumologie (Pädiatrie)

UniBE Contributor:

Regamey, Nicolas and Kieninger, Elisabeth

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0091-6749

Publisher:

Mosby

Language:

English

Submitter:

André Schaller

Date Deposited:

13 Apr 2015 15:15

Last Modified:

03 Jul 2015 01:30

Publisher DOI:

10.1016/j.jaci.2014.11.039

PubMed ID:

25630941

Uncontrolled Keywords:

Rhinovirus; T(H)2 inflammation; asthma; asthma exacerbation; atopy; cytokine; innate immunity; interferon; suppressor of cytokine signalingunity interferon suppressor of cytokine signaling

BORIS DOI:

10.7892/boris.66604

URI:

https://boris.unibe.ch/id/eprint/66604

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