Shikonin Controls the Differentiation of CD4 + CD25 + Regulatory T Cells by Inhibiting AKT/mTOR Pathway
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ORIGINAL ARTICLE
Shikonin Controls the Differentiation of CD4+CD25+ Regulatory T Cells by Inhibiting AKT/mTOR Pathway Xiaolan Zhang,1,2 Jianping Li,3 Yajie Yu,1 Peng Lian,4 Xinghua Gao,1 Yuanyuan Xu,1 and Long Geng1,5
CD4+CD25+ regulatory T (Treg) cells maintain the function of immune tolerance and the balance of immune cells. Defects in the number and function of Treg cells can induce the development and progression of inflammatory disease. Shikonin, the main active ingredient of Lithospermum, has anti-inflammatory and anti-tumor effects. Shikonin is also an effective drug for the treatment of psoriasis, which is a chronic inflammatory skin disease. However, the underlying mechanism is not yet clear. To evaluate the role of shikonin on the induction of Treg cells, we tested the number and function of Treg cells in vivo and in vitro. Shikonin can effectively promote the differentiation of iTreg cells by inhibiting the AKT/mTOR pathway in vitro. Moreover, in vivo, intragastrically administered shikonin effectively improved lesions in mice with imiquimod-induced psoriasis and increased the number of iTreg cells in the spleen and their secretion. Shikonin significantly increases the expression of Foxp3mRNA in skin of the psorisic mice. Therefore, we expect that shikonin can prevent the development of inflammation and treat psoriasis by regulating iTreg cells. Novel ideas for the treatment of psoriasis are also proposed. Abstract—
KEY WORDS: CD4+CD25+ regulatory T cells; shikonin; psoriasis.
INTRODUCTION CD4+CD25+ regulatory T (Treg) cells, as a subset of CD4 T lymphocytes, were first described as inhibitory cells in 1970 by Gershon [1]. Treg cells are characterized by continuously high levels of CD4 and CD25 expression, and the key transcription factor is the Foxkhead-family +
1
Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, 110001, China 2 Department of Dermatology, The first affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China 3 Liaoning Blood Center, Shenyang, 110001, China 4 Jinzhou City Animal Disease Control and Prevention Center, Jinzhou, 120001, China 5 To whom correspondence should be addressed at Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, 110001, China. E-mail: [email protected]
transcription factor FOXP3. Surface molecules on Treg cells include cytotoxic T lymphocyte antigen-4 (CTLA-4), glucocorticoid-induced TNF receptor-related (GITR) and so on. Regulatory T cells maintain immune homeostasis under normal physiological or pathological conditions [2– 4]. Regulatory T cells are divided based on origin into natural regulatory T cells (nTreg cells) from the thymus and induced Treg (iTreg) cells derived from peripheral lymphoid tissues. Among these, iTreg cells can be induced upon stimulation by peripheral antigens and sustained stimulation by relevant cytokines such as TGF-β1 [5]. Multiple signal transduction pathways are involved in regulating this process of iTreg cell differentiation, such as the IL-2-Stat5, T
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