J Immunol
Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London SE1 9RT, United Kingdom;
Published: February 2019
Glucocorticoids are known to increase production of the anti-inflammatory cytokine IL-10, and this action is associated with their clinical efficacy in asthmatics. However, glucocorticoids also enhance the synthesis of IL-17A by PBMCs, which, in excess, is associated with increased asthma severity and glucocorticoid-refractory disease. In this study, we show that the glucocorticoid dexamethasone significantly increased IL-10 production by human memory CD4 T cells from healthy donors, as assessed by intracellular cytokine staining. In addition, dexamethasone increased production of IL-17A, IL-17F, and IL-22, with the most striking enhancement in cells coproducing Th17-associated cytokines together with IL-10. Of note, an increase in IFN-γIL-10 cells was also observed despite overall downregulation of IFN-γ production. These dexamethasone-driven IL-10 cells, and predominantly the IL-17IL-10 double-producing cells, were markedly refractory to the inhibitory effect of dexamethasone on proliferation and IL-2Rα expression, which facilitated their preferential IL-2-dependent expansion. Although lower concentrations of exogenous IL-2 promoted IL-10 cells coproducing proinflammatory cytokines, higher IL-2 doses, both alone and in combination with dexamethasone, increased the proportion of single IL-10 T cells. Thus, glucocorticoid-induced IL-10 is only accompanied by an increase of IL-17 in a low IL-2 setting, which is, nevertheless, likely to be protective owing to the induction of regulatory IL-17IL-10-coproducing 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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341182 | PMC |
http://dx.doi.org/10.4049/jimmunol.1800697 | DOI Listing |
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