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Abstract
Dexmedetomidine is an α2 adrenergic receptor agonist that has been reported to modulate the polarization of CD4+ T cells. However, the underlying mechanisms by which dexmedetomidine induces T-helper 1 (Th1) cell differentiation remain poorly understood. The aim of this study was to explore the potential mechanisms through which dexmedetomidine can induce Th1 cell differentiation. Purified CD4+ T cells were stimulated with anti-CD3/anti-CD28 and then treated with dexmedetomidine. Flow cytometry analysis was adopted to measure the concentration of Th1 cells. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qPCR) were performed to detect protein levels and mRNA expression, respectively, of IFN-γ and IL-4. Western blotting was used to determine the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and T-bet expression. The Th1 cell subset and IFN-γ levels were elevated in the dexmedetomidine-induced CD4+ T cells. Dexmedetomidine enhanced the phosphorylation of STAT1 and the expression of T-bet in the CD4+ T cells. Atipamezole (an α2 adrenergic antagonist) and fludarabine (a STAT1 inhibitor) reversed the dexmedetomidine-induced Th1 cell differentiation. These results suggested that dexmedetomidine induced Th1 cell differentiation via the STAT1-T-bet signaling pathway.
Highlights
Surgical trauma and tumor microenvironments can suppress the innate immunity of patients, as well as increase the postoperative infection rate and tumor metastasis by inducing CD4+ T cells toward a T-helper 2 (Th2) cell fate [1, 2]
Dexmedetomidine increased the concentration of T-helper 1 (Th1) cells in the CD4+ T cells, especially at a concentration of 0.1 nM, while it had no effect on the concentration of Th2 cells. These results suggest that dexmedetomidine regulates the polarization of CD4+ T cells, inducing Th1 differentiation but not Th2 differentiation
The protein expression of T-bet was monitored by western blots to clarify further that dexmedetomidine stimulation raised T-bet protein levels (Figure 3(b)). These findings showed that dexmedetomidine-induced Th1 cell differentiation may be mediated by enhancing signal transducer and activator of transcription 1 (STAT1)– T-bet signaling
Summary
Surgical trauma and tumor microenvironments can suppress the innate immunity of patients, as well as increase the postoperative infection rate and tumor metastasis by inducing CD4+ T cells toward a T-helper 2 (Th2) cell fate [1, 2]. Regulating Th1 cell fate enhances the function of natural killer cells to inhibit the growth of breast cancer cells [3] and relieves the symptoms of infection [4]. Clinical studies [6, 7] found that dexmedetomidine increases serum IFN-γ, suggesting enhancement of Th1 cell fate in surgery patients. Dexmedetomidine may regulate Th1 cell differentiation to relieve the immunosuppressant effect induced by surgical trauma, but the underlying mechanism remains unclear
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