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 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.

Keywords: IL-13; IL-2; Th2 cells; apoptosis; asthma; steroid.