Abstract
Interleukin-37 (IL-37) possesses the function of down-regulate systemic and local inflammation. It is unknown whether IL-37 is expressed in human regulatory T cells (Tregs) and its role in modulating the immune response of Tregs. In the present study, cell surface molecules and secretory cytokines were analyzed in order to determine the function of IL-37 in regulating inhibitory effect of human CD4+CD25+Tregs. Meanwhile, the effects of IL-37 on T cell differentiation and proliferation as co-culture of CD4+CD25+Treg/CD4+CD25−T cell were also investigated. It was showed that IL-37 was expressed in cytoplasm of CD4+CD25+Tregs, and the levels of IL-37 were gradually elevated with the enhanced activity of CD4+CD25+Tregs. Secretory cytokines such as transforming growth factor (TGF)-β and interleukin (IL)-10, and expressions of cell surface molecules, including forkhead/winged helix transcription factor p3 (FOXP3) and cytotoxic T-lymphocyte associated antigen (CTLA)-4, were significantly decreased when IL-37 gene was silenced by siRNA. Furthermore, down-regulation of IL-37 expression in human CD4+CD25+Tregs obviously promoted proliferation of co-cultured T cell and differentiation, together with observably enhancement of IL-2 formation. These results demonstrated that IL-37 might manifest as a critical protein involving in immunosuppression of human CD4+CD25+Tregs.
Highlights
It is well accepted that regulatory T cells (Tregs) are crucial to the proper maintenance of immune self-tolerance and homeostasis[1,2]
After 72 h sustaining stimulation of human Treg expander, green fluorescence was observed in the cytoplasm of the 72 h group of CD4+CD25+Tregs. These findings proved that IL-37 was poorly expressed in inactive CD4+CD25+Tregs, with gradually increased activity of CD4+CD25+Tregs, IL-37 was markedly expressed
IL-37 is the 7th factor (IL-1F7) of interleukin-1 family (IL-1F), and it is widely expressed in human organs and tissues
Summary
It is well accepted that regulatory T cells (Tregs) are crucial to the proper maintenance of immune self-tolerance and homeostasis[1,2]. IL-37, which is the seventh interleukin factor of interleukin 1 family (IL-1F7), has the ability to down-regulate systemic and local inflammation by lowering levels of pro-inflammatory mediators[11,12]. It is involved in both innate and adaptive immunity. IL-37 suppresses the production of various pro-inflammatory cytokines, including IL-1α , IL-1β , IL-6, IL-12, granulocyte colony-stimulating factor (G-SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and TNF-α. This property does not depend on the production of anti-inflammatory cytokines, such as IL-1012. The objective of this study was to identify IL-37expression in human CD4+CD25+Tregs with Western blotting and confocal laser scanning microscopy, and further investigate the potential effect of IL-37 on Treg-mediated immunosuppression in vitro
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