Interleukin (IL)-15 plays an important role in natural killer (NK) and CD8+ T-cell proliferation and function and is more effective than IL-2 for tumor immunotherapy. The trans-presentation of IL-15 by neighboring cells is more effective for NK cell activation than its soluble IL-15. In this study, the fusion protein dsNKG2D-IL-15, which consisted of two identical extracellular domains of human NKG2D coupled to human IL-15 via a linker, was engineered in Escherichia coli. DsNKG2D-IL-15 could efficiently bind to major histocompatibility complex class I chain-related protein A (MICA) of human tumor cells with the two NKG2D domains and trans-present IL-15 to NK or CD8+ T cells. We transplanted human gastric cancer (SGC-7901) cells into nude mice and mouse melanoma cells with ectopic expression of MICA (B16BL6-MICA) into C57BL/6 mice. Then, we studied the anti-tumor effects mediated by dsNKG2D-IL-15 in the two xenografted tumor models. Human dsNKG2D-IL-15 exhibited higher efficiency than IL-15 in suppressing gastric cancer growth. Exogenous human dsNKG2D-IL-15 was centrally distributed in the mouse tumor tissues based on in vivo live imaging. The frequencies of human CD56+ cells infiltrated into the tumor tissues following the injection of peripheral blood mononuclear cells into nude mice bearing human gastric cancer were significantly increased by human dsNKG2D-IL-15 treatment. Human dsNKG2D-IL-15 also delayed the growth of transplanted melanoma (B16BL6-MICA) by activating and recruiting mouse NK and CD8+ T cells. The anti-melanoma effect of human dsNKG2D-IL-15 in C57BL/6 mice was mostly decreased by the in vivo depletion of mouse NK cells. These data highlight the potential use of human dsNKG2D-IL-15 for tumor therapy.Cellular& Molecular Immunology advance online publication, 14 September 2015; doi:10.1038/cmi.2015.81.
This study is designed to investigate the changes of NKG2D expression on CD8 + T cells and CD3 + T cells expression in acute phase of KD were significantly lower than those in normal controls (P < 0.05), and the levels of NKG2D expression in the patients with coronary artery lesion (KD-CAL + ) were lower than those in patients with KD-CAL À . There was an upregulated tendency after treatment with IVIG. We found higher expression levels of proinflammatory cytokines from MC, such as IL-1b, IL-6 and TNF-a in patients with KD compared with the healthy controls (P < 0.05). The concentrations of IL-7 and IL-15 were significantly decreased in acute phase of KD (P < 0.05) and to some extent elevated after therapy with IVIG (P < 0.05), while antagonistic cytokines like IFN-c were increased in acute phase of KD (P < 0.05) and reduced after therapy with IVIG (P < 0.05). These results suggest that aberrantly decreased levels of NKG2D expression on NK cells and CD8 + T cells might be one of the factors led to disturbed immunological function in patients with KD. Cytokines milieu could be important factors causing reduced expression of NKG2D.
Background:
Cordycepin (Cor), one of the major bioactive components of the traditional
Chinese medicine Cordyceps militaris, has been used in clinical practice for several years. However,
its neuroprotective effect remains unknown.
Aim:
The purpose of the study was to evaluate the neuroprotective effects of Cor using a rotenoneinduced
Parkinson’s Disease (PD) rat model and to delineate the possible associated molecular mechanisms.
Methods:
In vivo, behavioural tests were performed based on the 10-point scale and grid tests. Levels
of dopamine and its metabolites in the striatum and the numbers of TH-positive neurons in the Substantia
Nigra pars compacta (SNpc) were investigated by high-performance liquid chromatography
with electrochemical detection and immunohistochemical staining, respectively. In vitro, cell apoptosis
rates and Mitochondrial Membrane Potential (MMP) were analysed by flow cytometry and the
mRNA and protein levels of Bax, Bcl-2, Bcl-xL, Cytochrome c (Cyt-c), and caspase-3 were determined
by quantitative real-time PCR and western blotting.
Results:
Showed that Cor significantly improved dyskinesia, increased the numbers of TH-positive
neurons in the SNpc, and maintained levels of dopamine and its metabolites in the striatum in rotenone-
induced PD rats. We also found that apoptosis was suppressed and the loss of MMP was reversed
with Cor treatment. Furthermore, Cor markedly down-regulated the expression of Bax, upregulated
Bcl-2 and Bcl-xL, inhibited the activation of caspase-3, and decreased the release of Cyt-c
from the mitochondria to the cytoplasm, as compared to those in the rotenone-treated group.
Conclusion:
Therefore, Cor protected dopamine neurons against rotenone-induced apoptosis by improving
mitochondrial dysfunction in a PD model, demonstrating its therapeutic potential for this disease.
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