IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?
Abstract Background Glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine expression and induce apoptosis. Asthma severity is associated with type 2 inflammation, circulating Th2 cells and higher GC requirements. Objective The aim of this study was to assess whe...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Wiley
2019-09-01
|
Series: | Immunity, Inflammation and Disease |
Subjects: | |
Online Access: | https://doi.org/10.1002/iid3.249 |
id |
doaj-9d285b63a36346adb27739339d6539aa |
---|---|
record_format |
Article |
spelling |
doaj-9d285b63a36346adb27739339d6539aa2020-11-25T03:04:00ZengWileyImmunity, Inflammation and Disease2050-45272019-09-017311212410.1002/iid3.249IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?Tharsan Kanagalingam0Lauren Solomon1Meerah Vijeyakumaran2Nami Shrestha Palikhe3Harissios Vliagoftis4Lisa Cameron5Department of Pathology and Laboratory Medicine Western University London Ontario CanadaDepartment of Pathology and Laboratory Medicine Western University London Ontario CanadaDepartment of Pathology and Laboratory Medicine Western University London Ontario CanadaDepartment of Medicine, and Alberta Respiratory Centre University of Alberta Edmonton Alberta CanadaDepartment of Medicine, and Alberta Respiratory Centre University of Alberta Edmonton Alberta CanadaDepartment of Pathology and Laboratory Medicine Western University London Ontario CanadaAbstract Background Glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine expression and induce apoptosis. Asthma severity is associated with type 2 inflammation, circulating Th2 cells and higher GC requirements. Objective The aim of this study was to assess whether ex vivo production of interleukin 2 (IL‐2), a T‐cell survival factor, associated with clinical features of asthma severity, the proportion of blood Th2 cells and Th2 cell responses to GC. Methods Peripheral blood from asthma patients (n = 18) was obtained and the proportion of Th2 cells determined by flow cytometry. Peripheral blood cells were activated with mitogen (24 hours) and supernatant levels of IL‐2 and IL‐13 measured by enzyme‐linked immunosorbent assay. In vitro differentiated Th2 cells were treated with dexamethasone (DEX) and IL‐2 and assessed for apoptosis by flow cytometry (annexin V). Level of messenger RNA (mRNA) for antiapoptotic (BCL‐2) and proapoptotic (BIM) genes, IL‐13, GC receptor (GR) and FKBP5 were determined by quantitative real‐time polymerase chain reaction. GR binding was assessed by chromatin immunoprecipitation. Results IL‐2 produced by activated peripheral blood cells correlated negatively with lung function and positively with a daily dose of inhaled GC. When patients were stratified based on IL‐2 level, high IL‐2 producers made more IL‐13 and had a higher proportion of circulating Th2 cells. In vitro, increasing the level of IL‐2 in the culture media was associated with resistance to DEX‐induced apoptosis, with more BCL‐2/less BIM mRNA. Th2 cells cultured in high IL‐2 had more IL‐13, less GR mRNA, showed reduced binding of the GR to FKBP5, a known GC‐induced gene, and required higher concentrations of DEX for cytokine suppression. Conclusions and Clinical Relevance IL‐2 downregulates Th2 cell responses to GC, supporting both their survival and pro‐inflammatory capacity. These results suggest that a patient's potential to produce IL‐2 may be a determinant in asthma severity.https://doi.org/10.1002/iid3.249apoptosisasthmaIL‐13IL‐2steroidTh2 cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tharsan Kanagalingam Lauren Solomon Meerah Vijeyakumaran Nami Shrestha Palikhe Harissios Vliagoftis Lisa Cameron |
spellingShingle |
Tharsan Kanagalingam Lauren Solomon Meerah Vijeyakumaran Nami Shrestha Palikhe Harissios Vliagoftis Lisa Cameron IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation? Immunity, Inflammation and Disease apoptosis asthma IL‐13 IL‐2 steroid Th2 cells |
author_facet |
Tharsan Kanagalingam Lauren Solomon Meerah Vijeyakumaran Nami Shrestha Palikhe Harissios Vliagoftis Lisa Cameron |
author_sort |
Tharsan Kanagalingam |
title |
IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation? |
title_short |
IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation? |
title_full |
IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation? |
title_fullStr |
IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation? |
title_full_unstemmed |
IL‐2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation? |
title_sort |
il‐2 modulates th2 cell responses to glucocorticosteroid: a cause of persistent type 2 inflammation? |
publisher |
Wiley |
series |
Immunity, Inflammation and Disease |
issn |
2050-4527 |
publishDate |
2019-09-01 |
description |
Abstract Background Glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine expression and induce apoptosis. Asthma severity is associated with type 2 inflammation, circulating Th2 cells and higher GC requirements. Objective The aim of this study was to assess whether ex vivo production of interleukin 2 (IL‐2), a T‐cell survival factor, associated with clinical features of asthma severity, the proportion of blood Th2 cells and Th2 cell responses to GC. Methods Peripheral blood from asthma patients (n = 18) was obtained and the proportion of Th2 cells determined by flow cytometry. Peripheral blood cells were activated with mitogen (24 hours) and supernatant levels of IL‐2 and IL‐13 measured by enzyme‐linked immunosorbent assay. In vitro differentiated Th2 cells were treated with dexamethasone (DEX) and IL‐2 and assessed for apoptosis by flow cytometry (annexin V). Level of messenger RNA (mRNA) for antiapoptotic (BCL‐2) and proapoptotic (BIM) genes, IL‐13, GC receptor (GR) and FKBP5 were determined by quantitative real‐time polymerase chain reaction. GR binding was assessed by chromatin immunoprecipitation. Results IL‐2 produced by activated peripheral blood cells correlated negatively with lung function and positively with a daily dose of inhaled GC. When patients were stratified based on IL‐2 level, high IL‐2 producers made more IL‐13 and had a higher proportion of circulating Th2 cells. In vitro, increasing the level of IL‐2 in the culture media was associated with resistance to DEX‐induced apoptosis, with more BCL‐2/less BIM mRNA. Th2 cells cultured in high IL‐2 had more IL‐13, less GR mRNA, showed reduced binding of the GR to FKBP5, a known GC‐induced gene, and required higher concentrations of DEX for cytokine suppression. Conclusions and Clinical Relevance IL‐2 downregulates Th2 cell responses to GC, supporting both their survival and pro‐inflammatory capacity. These results suggest that a patient's potential to produce IL‐2 may be a determinant in asthma severity. |
topic |
apoptosis asthma IL‐13 IL‐2 steroid Th2 cells |
url |
https://doi.org/10.1002/iid3.249 |
work_keys_str_mv |
AT tharsankanagalingam il2modulatesth2cellresponsestoglucocorticosteroidacauseofpersistenttype2inflammation AT laurensolomon il2modulatesth2cellresponsestoglucocorticosteroidacauseofpersistenttype2inflammation AT meerahvijeyakumaran il2modulatesth2cellresponsestoglucocorticosteroidacauseofpersistenttype2inflammation AT namishresthapalikhe il2modulatesth2cellresponsestoglucocorticosteroidacauseofpersistenttype2inflammation AT harissiosvliagoftis il2modulatesth2cellresponsestoglucocorticosteroidacauseofpersistenttype2inflammation AT lisacameron il2modulatesth2cellresponsestoglucocorticosteroidacauseofpersistenttype2inflammation |
_version_ |
1724683385955155968 |