期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 38, 期 9, 页码 2412-2418出版社
WILEY-BLACKWELL
DOI: 10.1002/eji.200838318
关键词
Foxp3; HIF-1; hypoxia; inflammation; regulatory T cells
类别
资金
- Israel Science Foundation [J.G.
- 832/06]
Recent data suggest that hypoxia and its principal molecular signature HIF-1 (hypoxia-inducing factor-1) may tune down inflammation by dictating anti-inflammatory programs. We tested the effects of hypoxia and HIF-1 alpha on the homeostasis of naturally occurring regulatory T cells (Treg) and their transcriptional activator Foxp3. Hypoxia induced a time-dependent increase in HIF-1 alpha in mouse and human T cells. Hypoxia upregulated the expression of Foxp3 in Jurkat T cells, human and murine mononuclear cells. The effects of hypoxia on Foxp3 expression were HIF-1 alpha-dependent as they were abolished upon transfection with short-interfering RNAs for HIF-1 alpha and promoted by HIF-1 alpha over-expression. Hypoxia increased the potency of Treg, as hypoxic CD4(+)CD25(+) lymphocytes were more effective than normoxic cells in suppressing the proliferation of CD4(+)CD25(-) effectors. In vivo expression of HIF-1 alpha achieved by hydrodynamic injection of the respective naked DNA similarly induced an increase in Foxp3 expression and an increase in the number of functionally active Foxp3(+)CD4(+)CD25(+) Treg. Thus, hypoxia dictates an anti-inflammatory program by driving expression of HIF-1 alpha that acts to increase the number and suppressive properties of naturally occurring CD4(+)CD25(+) Treg.
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