Lin Sun

Nanjing University, Nanjing, Jiangsu Sheng, China

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Publications (4)15.7 Total impact

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    ABSTRACT: Aberrant CD40 expression by dendritic cells (DCs), induced by microbial stimuli, such as CpG, contributes to the pathogenesis of many human/murine diseases, particularly autoimmune and inflammatory diseases. Given the importance of CD40 in these diseases, and the contribution of DCs to the diseases process, it is very important to investigate the mechanisms of CD40 expression induced by CpG on DCs. In this study, we made the observation that CpG-B is a potent inducer on CD40 expression on murine bone marrow-derived DCs. Based on this finding, we undertook an analysis of the molecular basis of CpG-induced CD40 expression on DCs. By using selective inhibitors, it was demonstrated that MAPKs (JNK and p38 MAPK, but not ERK) and NF-κB were involved in CpG-induced CD40 expression on DCs. In addition, RNA interference analysis revealed that IRF8 was a key transcription factor in the basal expression of CD40 upon CpG stimulation. Moreover, up-regulating miRNA-146a in DCs effectively decreased CD40 expression by targeting TRAF6 and IRAK1. Thus, our results have elucidated the molecular mechanisms underlying CpG-induced CD40 expression and DC maturation.
    Autoimmunity 12/2012; · 2.77 Impact Factor
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    ABSTRACT: Chaetoglobosin F (Cha F), a cytochalasan-based alkaloid, was obtained from the EtOAc extract of a solid culture of Chaetomium globosum IFB-E019. Dendritic cells (DCs), the most potent antigen presenting cells, are considered as the major target in the modulation of excessive immune responses. Recognition of CpG-DNA by Toll-like receptor 9 (TLR9) on DCs is an important step in the pathogenesis of autoimmune diseases. However, the effect of Cha F on the maturation and immunostimulatory function of CpG-stimulated DCs remains unclear. This study investigated the effects of Cha F on bone marrow (BM)-derived DCs. We found that Cha F inhibits the CpG-induced DCs maturation and function by suppressing the expression of surface molecules (CD40, CD80, CD86 and MHC-II), reducing the production of cytokines and chemokines (IL-12 and CXCL-10), inhibiting the CpG-induced DCs-elicited allogeneic T-cell proliferation, and impairing the migration ability to chemokines. The Cha F-treated DCs were highly efficient at Ag capture, via mannose receptor-mediated endocytosis. Additionally, Cha F was also demonstrated to inhibit CpG-induced activation of MAPKs (p38 and JNK, but not ERK) and the nuclear translocation of NF-κB and STAT1. Furthermore, we confirmed that Cha F was able to suppress TLR9 expression of CpG-induced DCs. Collectively, these findings provide novel insight into the immunopharmacological functions of Cha F, especially with regard to their impact on CpG-induced DCs. These immunosuppressive properties of Cha F may prove useful in controlling DCs-associated autoimmune and/or inflammatory diseases.
    Immunobiology 05/2012; · 2.81 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) are implicated in the induction of autoimmune diseases and exist in lesions associated with several autoimmune inflammatory diseases. Chaeoglobosin Fex (Cha Fex), a cytochalasan-based alkaloid, was isolated from marine-derived endophytic fungus Chaetomium globosum QEN-14. In the present study, we evaluated the effect of Cha Fex on poly(I:C)-induced bone marrow-derived DCs. The results showed that Cha Fex attenuated the production of IFN-β both at the mRNA and protein level in poly(I:C)-induced DCs. Cha Fex markedly inhibited the maturation and function of the DCs with a reduced capacity to uptake antigens and low level of expression of costimulatory molecules. Moreover, Cha Fex abrogated the ability of poly(I:C)-induced DCs to promotion of T cell proliferation, Furthermore, Cha Fex inhibited the phosphorylation of IκB-α and IRF-3 in poly(I:C)-induced DCs. Cha Fex also reduced the phosphorylation of p38 and JNK, without affecting ERK1/2. These data demonstrate that that Cha Fex can exhibit an immunosuppressive effect on mouse bone marrow-derived DCs (BMDCs) via TLR3 signaling, which suggests potential application of Cha Fex in the treatment of autoimmune inflammatory diseases.
    Molecular Immunology 03/2012; 51(2):150-8. · 2.65 Impact Factor
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    ABSTRACT: The human immune system exhibits sexual dimorphism in autoimmune diseases such as systemic lupus erythematosus (SLE). Female sex hormones, including 17β-estradiol, are strongly implicated in the gender bias in SLE. CD40 is a costimulatory molecule and plays a crucial role in modulating the immune response of effector cells. We have previously shown that 17β-estradiol up-regulated CD40 expression and altered minichromosome maintenance protein 6 (MCM6) gene expression in dendritic cells (DCs). The mechanism of the correlation between CD40 and MCM6 in the presence of 17β-estradiol remains unknown. This study was undertaken to elucidate this mechanism and to explain the role of MCM6 in the gender bias in SLE. Bone marrow-derived DCs transfected with small interfering RNA (siRNA) for MCM6 were treated with 17β-estradiol in the absence or presence of CpG. The expression levels of costimulatory molecules, activity of MAPKs, and levels of MCM6 protein were measured. Moreover, the functions of DCs, including proliferation, apoptosis, endocytosis, and cytokine production, were analyzed. In addition, levels of messenger RNA for MCM6 were detected in DCs purified from SLE patients. Regardless of the presence or absence of CpG, 17β-estradiol induced CD40 expression via the activation of p38 and JNK, but not ERK. The activation of p38 and JNK enhanced MCM6 expression, which then induced CD40 expression. Suppression of MCM6 in DCs abolished the up-regulation of 17β-estradiol-induced CD40 expression. Importantly, MCM6 expression was significantly increased in SLE patients compared with healthy controls. Our findings indicate that 17β-estradiol induces CD40 expression in DCs via p38 and JNK MAPKs in an MCM6-dependent manner. MCM6 may be a critical mediator of sex-based differences in autoimmune disease.
    Arthritis & Rheumatology 05/2011; 63(8):2425-35. · 7.48 Impact Factor