Modulation of Radiation-Induced Disturbances of Antioxidant Defense Systems by Ginsan

There are numerous studies to indicate that irradiation induces reactive oxygen species (ROS), which play an important causative role in radiation damage of the cell. We evaluated the effects of ginsan, a polysaccharide fraction extracted from Panax ginseng, on the γ-radiation induced alterations of some antioxidant systems in the spleen of Balb/c mice. On the 5th day after sublethal whole-body irradiation, homogenized spleen tissues of the irradiated mice expressed only marginally increased mRNA levels of Mn-SOD (superoxide dimutase) in contrast to Cu/Zn-SOD, however, catalase mRNA was decreased by ∼50% of the control. In vivo treatment of non-irradiated mice with ginsan (100 mg kg(−1), intraperitoneal administration) had no significant effect, except for glutathione peroxidase (GPx) mRNA, which increased to 144% from the control. However, the combination of irradiation with ginsan effectively increased the SODs and GPx transcription as well as their protein expressions and enzyme activities. In addition, the expression of heme oxygenase-1 and non-protein thiol induced by irradiation was normalized by the treatment of ginsan. Evidence indicated that transforming growth factor-β and other important cytokines such as IL-1, TNF and IFN-γ might be involved in evoking the antioxidant enzymes. Therefore, we propose that the modulation of antioxidant enzymes by ginsan was partly responsible for protecting the animal from radiation, and could be applied as a therapeutic remedy for various ROS-related diseases

NFAT1 and NFκB regulates expression of the common γ-chain cytokine receptor in activated T cells

Abstract Introduction Cytokines of the common γ chain (γc) family are critical for the development, differentiation, and survival of T lineage cells. Cytokines play key roles in immunodeficiencies, autoimmune diseases, allergies, and cancer. Although γc is considered an assistant receptor to transmit cytokine signals and is an indispensable receptor in the immune system, its regulatory mechanism is not yet well understood. Objective This study focused on the molecular mechanisms that γc expression in T cells is regulated under T cell receptor (TCR) stimulation. Methods The γc expression in TCR-stimulated T cells was determined by flow cytometry, western blot and quantitative RT-PCR. The regulatory mechanism of γc expression in activated T cells was examined by promoter-luciferase assay and chromatin immunoprecipitation assays. NFAT1 and NFκB deficient cells generated using CRISPR-Cas9 and specific inhibitors were used to examine their role in regulation of γc expression. Specific binding motif was confirmed by γc promotor mutant cells generated using CRISPR-Cas9. IL-7TgγcTg mice were used to examine regulatory role of γc in cytokine signaling. Results We found that activated T cells significantly upregulated γc expression, wherein NFAT1 and NFκB were key in transcriptional upregulation via T cell receptor stimulation. Also, we identified the functional binding site of the γc promoter and the synergistic effect of NFAT1 and NFκB in the regulation of γc expression. Increased γc expression inhibited IL-7 signaling and rescued lymphoproliferative disorder in an IL-7Tg animal model, providing novel insights into T cell homeostasis. Conclusion Our results indicate functional cooperation between NFAT1 and NFκB in upregulating γc expression in activated T cells. As γc expression also regulates γc cytokine responsiveness, our study suggests that γc expression should be considered as one of the regulators in γc cytokine signaling and the development of T cell immunotherapies. Video Abstrac