Rhinovirus (RV) infection is responsible for most asthma exacerbations. Defective RV induced interferon (IFN)-β and IFN-λs has been observed in asthmatic bronchial epithelial cells (BECs). Suppressors of cytokine signalling (SOCS) are negative regulators of cytokine signalling including IFNs. This study investigated the role of SOCS in the regulation of RV infection in vitro and in vivo using human BECs (HBECs) and mouse models of RV infection to determine whether SOCS were responsible for impaired IFN ex vivo. This was accomplished by measuring SOCS and IFN-β/λ mRNA and protein expression and IFN promoter activation. RV induced SOCS1 and SOCS3 mRNA and protein in HBECs and in lung from C57/Bl6 mice and SOCS1 mRNA in mouse BAL macrophages ex vivo. SOCS1 and SOCS3 acted as negative regulators of RV induced IFN-β and IFN-λ1 promoter activation in HBECs. SOCS1 protein was increased in bronchial biopsies from mild asthmatics compared to non-asthmatics. SOCS1 mRNA expression was increased in HBECs from severe asthmatic children compared to non-asthmatics. Increased SOCS1 mRNA levels negatively correlated with RV1B induced IFN-λ mRNA and positively correlated with RV16 release. RV1B induced IFN-β mRNA was increased in BAL macrophages from SOCS1-/- IFN-γ-/- mice compared to IFN-γ-/- mice. Upon induction of SOCS1 by IL-13 in IFN-γ-/- mice and subsequent RV1B infection, reduced IFN-α and IFN-λ protein in BAL was observed compared to SOCS1-/- IFN-γ-/- mice. This is the first report investigating SOCS1 and SOCS3 in relation to RV induced IFN responses. RV induced SOCS1 and SOCS3 in vitro, ex vivo and in vivo. SOCS3 negatively regulated RV induced IFN responses in vitro. SOCS1 negatively regulated RV induced IFN responses in vitro, ex vivo and in vivo. This is the first report finding an association between increased expression of a gene, SOCS1, with impaired IFN production and increased RV release in asthma.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:555942 |
| Date | January 2012 |
| Creators | Gielen, Vera |
| Contributors | Johnston, Sebastian ; Edwards, Michael |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/9661 |
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