Memory CD4+ T cells were stimulated in the presence of vehicle control (white) or 1 10?7M dexamethasone (Dex; gray). is, nevertheless, likely to be protective owing to the induction of regulatory IL-17+IL-10+Ccoproducing cells. These findings open new avenues of investigation with respect to the role of IL-2 in glucocorticoid responsiveness that have potential implications for optimizing the benefit/risk ratio of glucocorticoids in the clinic. Introduction Glucocorticoids are a class of lipophilic steroid hormones that are synthesized endogenously by the adrenal cortex. They can bind to the glucocorticoid receptor (GR), which is expressed by most nucleated cells, and trigger a broad range of effects via transactivation and Hsh155 transrepression in addition to other GR-independent actions. Their actions are pleiotropic, affecting various physiological processes including development, metabolism, and inflammation, and, as such, synthetic glucocorticoids have been used in the clinic since 1948 (1). Glucocorticoids remain the most important anti-inflammatory pharmacotherapy in modern medicine despite their untoward side effects. Their anti-inflammatory properties result from their transrepression of proinflammatory genes such as IL-1 and IL-4, transactivation of anti-inflammatory genes, and upregulation of the frequency and activity of regulatory T cells (Tregs) (2). In vivo glucocorticoids have been shown to increase serum FX1 levels of the anti-inflammatory cytokine IL-10 (3) as well FX1 as the synthesis of IL-10 by cells locally in the airways (4). Furthermore, the synthetic glucocorticoid dexamethasone enhances the concentration of IL-10 in cultures of FX1 PBMCs, CD4+, and CD8+ T cells isolated from healthy humans in vitro (5C8). The importance of glucocorticoid-induced IL-10 is highlighted by studies in patients with severe steroid-resistant (SR) asthma, who represent a profound clinical challenge for disease management. SR asthma patients have a defect in the dexamethasone-driven IL-10 response (6, 9, 10) and heightened levels of IL-17A; indeed, levels of IL-17A inversely correlate with lung function (11) and are significantly elevated in the peripheral blood (6, 7, 12), sputum (13), serum (14, 15), and bronchial alveolar lining fluid (16, FX1 17) of patients with severe asthma, with the greatest levels observed in patients with SR disease (7). Levels of IL-17A are also elevated in mouse models of airway hyperresponsiveness in which Th17 cells drive pathological conditions (18, 19). Th17 cells are critical for protecting against mucosal and fungal infections; however, they have also been implicated in various immune-mediated diseases (20). More specifically, cells that differentiate in the presence of IL-23 and TGF-3 to coexpress Th1- and Th17-associated molecules have been shown to drive experimental autoimmune encephalomyelitis in mice (21, 22). Ramesh et al. (23) showed that human peripheral blood CD4+ T cells cultured with IL-23 produced IL-17A, IL-17F, IL-22, and IFN-, but not IL-10. However, distinct Th17 phenotypes exist; for example, Zielinski et al. (24) observed = 4); data assessed by a paired test. (C) The percentage of IL-10+ cells in memory CD4+ T cell cultures (= 9); data assessed by repeated measures one-way ANOVA with Tukey multiple comparisons test. * 0.05, **** 0.0001. Dexamethasone enhances production of IL-10 and IL-17A but not IFN- or IL-4 The kinetics of the dexamethasone-driven IL-10 response was next investigated directly in memory CD4+ T cells stimulated over a 6-d culture period (Fig. 2). In the absence of dexamethasone, the frequency of IL-10Cproducing cells reduced over time. In contrast, addition of 10?7M dexamethasone significantly increased the frequency of IL-10+ cells by day 5, although not at earlier time points. The proportion of IL-17A+ cells gradually increased with time and dexamethasone significantly, albeit more modestly, further enhanced the frequency of IL-17A+ T cells on days 5 and 6 of culture (Fig. 2A). In contrast, expression of IFN-, IL-4, and IL-2 was reduced or unaltered by dexamethasone throughout the culture (Fig. 2A, ?,2B).2B). These findings are in keeping with our previous findings (6, 7, 12) and further demonstrate that memory CD4+ T cells are the cellular source of both IL-10 and IL-17A following dexamethasone treatment. Open in a separate window FIGURE 2. Glucocorticoids increase expression of IL-10 and IL-17A, but not IFN-, IL-4, or IL-2, in memory CD4+ T cell cultures. Memory CD4+ T cells were stimulated in the presence of vehicle control (gray) or 1 10?7M dexamethasone (black; Dex). On the indicated.
Memory CD4+ T cells were stimulated in the presence of vehicle control (white) or 1 10?7M dexamethasone (Dex; gray)
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