IL-2 modulates Th2 cell responses to glucocorticosteroid: A cause of persistent type 2 inflammation?

Authors:
Tharsan Kanagalingam
Tharsan Kanagalingam
University of Toronto
Lauren Solomon
Lauren Solomon
University of Western Ontario
Canada
Nami Shrestha Palikhe
Nami Shrestha Palikhe
Ajou University School of Medicine
South Korea
Harissios Vliagoftis
Harissios Vliagoftis
University of Alberta
Canada
Lisa Cameron
Lisa Cameron
International Food Policy Research Institute

Immun Inflamm Dis 2019 Apr 17. Epub 2019 Apr 17.

Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.

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.

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Source
http://dx.doi.org/10.1002/iid3.249DOI Listing
April 2019
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