The role of STAT6 in the regulation of IL-4 and IL-13 mediated responses in Bronchial epithelial cells in asthma
The role of STAT6 in the regulation of IL-4 and IL-13 mediated responses in Bronchial epithelial cells in asthma
Immunochemistry applied to bronchial biopsies demonstrated the expression of STAT6 and one of its upstream activators JAK1 in the bronchial epithelium. In severe asthma, epithelial STAT6 expression was significantly increased when compared to with mild asthma (P=0.001) and normal controls (P=0.037). Furthermore, for the first time, this study identified expression of mRNA encoding a dominant negative isoform of STAT6 in primary bronchial epithelial cells, but no relationship between expression and disease status could be identified. As no studies have demonstrated a mechanism through which IL-4 might contribute airway wall remodelling, the effect of IL-4 on epithelial TGFβ2 release and the involvement of STAT6 in this process was assessed. Treatment of H292 cells with 1.5nM IL-4 significantly increased TGFβ2 release from 69± 10 to 118±27 pg/4x105 cells (n=8, P=0.034) at 48 hours. Using TaqManTM real-time PCR, increases in TGFβ mRNA production were not observed until 48 hours post treatment (from 0.817±0.12 pg/4x105 cells in untreated cells to 1.41±0.19 pg/3x105 cells following stimulation with 1.5nM IL-4, (n=5, P=0.013)). To investigate the involvement of TGFβ processing enzymes in this delayed response, the effects of a matrix metalloproteinase inhibitor (MMPI) on TGFβ2 release and transcription was assessed. In the presence of this inhibitor, IL-4 failed to induce TGFβ2 release or mRNA synthesis, however, the MMPI inhibitor alone promoted both TGFβ gene activation and protein release.
In conclusion, this study has shown that STAT6 expression is increased in the bronchial epithelium of severe asthmatic subjects. A possible site of interaction between the Th2 cytokines and airway wall remodelling in asthma is further suggested by the novel finding that IL-4 induced TGFβ2 release from the bronchial epithelial cells in a STAT6 dependent manner. This effect appeared to be indirect and may involve the activity of an MMP. As TGFβ is considered to be a central co-ordinator of profibrotic responses, the ability of IL-4 to promote TGFβ release and the involvement of STAT6 in this response may be amplified in asthmatic subjects, where this transcription factor is expressed at increased levels.
University of Southampton
Mullings, Rebecca E
9d2b0339-fa90-4689-ba5e-66d5649c3ee8
2002
Mullings, Rebecca E
9d2b0339-fa90-4689-ba5e-66d5649c3ee8
Mullings, Rebecca E
(2002)
The role of STAT6 in the regulation of IL-4 and IL-13 mediated responses in Bronchial epithelial cells in asthma.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Immunochemistry applied to bronchial biopsies demonstrated the expression of STAT6 and one of its upstream activators JAK1 in the bronchial epithelium. In severe asthma, epithelial STAT6 expression was significantly increased when compared to with mild asthma (P=0.001) and normal controls (P=0.037). Furthermore, for the first time, this study identified expression of mRNA encoding a dominant negative isoform of STAT6 in primary bronchial epithelial cells, but no relationship between expression and disease status could be identified. As no studies have demonstrated a mechanism through which IL-4 might contribute airway wall remodelling, the effect of IL-4 on epithelial TGFβ2 release and the involvement of STAT6 in this process was assessed. Treatment of H292 cells with 1.5nM IL-4 significantly increased TGFβ2 release from 69± 10 to 118±27 pg/4x105 cells (n=8, P=0.034) at 48 hours. Using TaqManTM real-time PCR, increases in TGFβ mRNA production were not observed until 48 hours post treatment (from 0.817±0.12 pg/4x105 cells in untreated cells to 1.41±0.19 pg/3x105 cells following stimulation with 1.5nM IL-4, (n=5, P=0.013)). To investigate the involvement of TGFβ processing enzymes in this delayed response, the effects of a matrix metalloproteinase inhibitor (MMPI) on TGFβ2 release and transcription was assessed. In the presence of this inhibitor, IL-4 failed to induce TGFβ2 release or mRNA synthesis, however, the MMPI inhibitor alone promoted both TGFβ gene activation and protein release.
In conclusion, this study has shown that STAT6 expression is increased in the bronchial epithelium of severe asthmatic subjects. A possible site of interaction between the Th2 cytokines and airway wall remodelling in asthma is further suggested by the novel finding that IL-4 induced TGFβ2 release from the bronchial epithelial cells in a STAT6 dependent manner. This effect appeared to be indirect and may involve the activity of an MMP. As TGFβ is considered to be a central co-ordinator of profibrotic responses, the ability of IL-4 to promote TGFβ release and the involvement of STAT6 in this response may be amplified in asthmatic subjects, where this transcription factor is expressed at increased levels.
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Published date: 2002
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Local EPrints ID: 464664
URI: http://eprints.soton.ac.uk/id/eprint/464664
PURE UUID: 5fb65a40-8b66-4fa5-bba9-17e8fc911920
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Date deposited: 04 Jul 2022 23:55
Last modified: 16 Mar 2024 19:41
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Author:
Rebecca E Mullings
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