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The different effects of indirubin on effector and CD4+CD25+ regulatory T cells in mice: potential implication for the treatment of autoimmune diseases

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Abstract

CD4+CD25+ regulatory T (Treg) cells play an essential role in the induction and maintenance of peripheral self-tolerance. Indirubin, a traditional Chinese medicine, was clinically used in the treatment of chronic myelocytic leukemia as well as some autoimmune diseases, including Alzheimer’s disease, diabetes, and so on. The effects of indirubin on CD4+CD25+Treg cells, which play a critical role in controlling autoimmunity, have not been addressed. In the present study, we observed the cell levels, phenotypes, and immunoregulatory function of CD4+CD25+Treg cells in indirubin-treated mice. Treatment with indirubin significantly enhanced the ratios of CD4+CD25+Treg cells or CD4+CD25+Foxp3+Treg cells to CD4+T cells in peripheral blood, lymph nodes, and spleens (P < 0.01 compared with control mice). CD4+CD25+Foxp3+Treg cells to CD4 single positive cells in the thymi of indirubin-treated mice were significantly higher than those in control mice. Furthermore, splenic CD4+CD25+Treg cells in indirubin-treated mice showed immunosuppressive ability on the immune response of T effector cells to alloantigens or mitogen as efficiently as the control CD4+CD25+Treg cells in vitro. The present studies indicate that CD4+CD25+Treg cells are more resistant to indirubin than effector T cells in vivo. The selectively enhanced CD4+CD25+Treg cell levels by indirubin made host to be more favorable for immune tolerance induction, which opened one possibility for indirubin to treat autoimmune diseases.

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Abbreviations

Treg:

regulatory T cells

AIDS:

acquired immune deficiency syndrome

DTH:

delayed-type hypersensitivity reaction

CTLA4:

cytotoxic T-lymphocyte-associated protein 4

FCM:

flow cytometry

FITC:

fluorescein isothiocyanate

Foxp3:

forkhead box protein 3

GITR:

glucocorticoid-induced tumor necrosis factor receptor

LNs:

lymph nodes

MFI:

median fluorescence intensity

MLR:

mixed lymphocytes reaction

PBMCs:

peripheral blood mononuclear cells

PE:

phycoerythrin

PI:

propidium iodide

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Acknowledgements

The authors wish to thank Ms. Jing Wang and Ms. Jianxia Peng for their expertise technical assistance, Ms. Qinghuan Li for her excellent laboratory management. This work was supported by grants from 973 Program 2006 CB 503803, National Natural Science Foundation of China (no. 30300312, no. 30470742, no. 30579779, and no. 30600259; M.H.), and Key Clinical Research Project of Public Health Ministry of China 2004-2006 (M.H.), National Natural Science Foundation for Distinguished Young Scholars (C03020504, Y.Z.), 100 Quality Vocational Colleges of Chinese Academy of Sciences (2003-85, Y.Z.), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars of State Education Ministry (2005-546, Y.Z.).

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Authors and Affiliations

  1. Hematology Oncology Center, Qilu Hospital, Shandong University, Jinan, 250012, China

    Aijun Zhang, Xuebin Ji & Ming Hou

  2. Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Datun Road Chaoyang 5, Beijing, 100101, China

    Aijun Zhang, Yanyan Qu, Baojun Zhang, Lianjun Zhang, Chun Zeng, Jianxia Peng & Yong Zhao

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  1. Aijun Zhang
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Correspondence to Yong Zhao.

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Zhang, A., Qu, Y., Zhang, B. et al. The different effects of indirubin on effector and CD4+CD25+ regulatory T cells in mice: potential implication for the treatment of autoimmune diseases. J Mol Med 85, 1263–1270 (2007). https://doi.org/10.1007/s00109-007-0235-9

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