Abstract
BackgroundGlucocorticosteroids (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.ObjectiveThe 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.MethodsPeripheral 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.ResultsIL‐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 RelevanceIL‐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.
Highlights
Asthma is a syndrome characterized by symptoms of diverse pathogenesis [1, 2]
While this study population consisted of only 4 severe asthmatics, our analysis does suggest this group is characterized by higher IL-2 production (56,380 pg/ml) compared to non-severe asthmatics (32,133 pg/ml, p = 0.07)
Our study reveals that peripheral blood cell production of IL-2 associates with poor lung function, increased GC usage and heightened type 2 inflammation
Summary
Asthma is a syndrome characterized by symptoms of diverse pathogenesis [1, 2]. Type 2 cytokines promote many of the processes responsible for the development of asthma and symptom manifestation. IL-4 is essential for Th2 cell differentiation and drives B cell isotype switching to IgE; IL-5 is a differentiation factor for eosinophils and mediates their egress from the bone marrow during allergic responses; IL-13 mediates airway hyperresponsiveness through inflammatory cell infiltration, smooth muscle contraction and epithelial secretions [reviewed in [3]]. These cytokines are produced by both type 2 CD4+ helper T cells (Th2 cells) [4, 5] and group 2 innate lymphoid cells (ILC2s) [6]. Since IL-2 is a T cell survival factor, we assessed whether IL-2 levels associate with the proportion of Th2 cells and/or correlate with clinical features of asthma severity
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