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이혜영,백상기 충남대학교 생물공학연구소 2003 생물공학연구지 Vol.9 No.1
The immune system of any organism must preserve a well balance between activation and inhibition. It must raise an effective immune response to target non-self molecules while not hampering the organism itself. Failure to maintain this balance will result in either immunodeficiency or autoimmunity. In many systemic autoimmune diseases, the production of pathogenic autoantibodies, released from B lymphocytes, has been the causes of autoimmunity, although the nature of the mechanism remains unclear. In recent years, several factors involved in the survival and inhibition of B lymphocytes were uncovered and found to be related to the several autoimmune diseases. Those are B lymphocytes inhibitory receptors and cytokines such as FcrRⅡ, CD22, PD-1, BAFF and BAFF-R. Investigating the genetic alterations and signalling components in these molecules and the consequences for the regulation of apoptosis/survival could show distinct ways to cure autoimmune diseases.
안현정,Hayyoung Lee,백상기 한국분자세포생물학회 2011 Molecules and cells Vol.31 No.6
We have previously shown that Ras mediates NO-induced BNIP3 expression via the MEK-ERK-HIF-1 pathway in mouse macrophages, and that NO-induced death results at least in part from the induction of BNIP3. In the present study, we describe another aspect of Ras regulation of BNIP3 expression in pancreatic cancer cells. Human BNIP3 promoter-driven luciferase activity was efficiently induced by activated Ras in AsPC-1, Miapaca-2, PK-1 and PANC-1 cells. However, expression of endoge-nous BNIP3 was not induced, and BNIP3 up-regulation by hypoxia was also inhibited. Treatment of the cells with the DNMT inhibitor, 5-aza-2-deoxycytidine, restored BNIP3 induction, indicating that DNA methylation of the BNIP3 promoter was respon-sible for the inhibition of BNIP3 induction. Furthermore, inhibition of the MEK pathway with U0126 reduced DNMT1 expression, but not that of DNMT3a and 3b, and restored the hypoxia-inducibility of BNIP3, suggesting that the DNA methylation of the BNIP3 promoter was mediated by DNMT1 via the MEK pathway.
대식세포주 RAW264.7에서 Nitric oxide에 의해 과발현되는 CD53의 기능분석
김태림,이혜영,김인규,백상기 충남대학교 생물공학연구소 2004 생물공학연구지 Vol.10 No.2
The CD53 antigen is a member of the tetraspanin membrane protein family that is expressed in the lymphoid-myeloid lineage. It is highly expressed in Radio-resistant tumor cells. Recently, it was reported that CD53 associates with the GSH-metabolizing protein γ-glutamyl transpeptidase. Its biological roles however remains unknown. Macrophages activated by microbial lipopolysaccharides (LPS) produce a burst of nitric oxide and reactive oxygen species. Nitric oxide plays important roles in macrophage activation as a toxic agent towards infectious organisms, an inducer or suppressor of apoptosis or an immunoregulator, whether nitric oxide can induce or inhibit apoptosis is highly dependent on different cell types at different stages of the inflammatory process. Using cDNA microarrays, we identified CD53 as one of the principal genes up-regulated by exposure of macrophages to LPS. We found that mRNA and protein levels of CD53 were increased by nitric oxide as well as LPS treatment in macrophages. Cells stably transfected with sense CD53 cDNA had lower levels of peroxide, and were more resistant to γ-irradiation. The stably transfected RAW264.7 cells with antisense CD53 recombination had the opposite properties. Activation of CD53 by cross-linking with monoclonal anti-CD53 antibody (OX-79) showed the expression of the inducible nitric oxide synthase. We propose that the induction of CD53 is one of major self-protection mechanisms of macrophages against LPS induced-oxidative stress and irradiation.
The Membrane-Bound Form of IL-17A Promotes the Growth and Tumorigenicity of Colon Cancer Cells
Van Anh Do Thi,박상민,Hayyoung Lee,김영상 한국분자세포생물학회 2016 Molecules and cells Vol.39 No.7
Interleukin-17A is a member of the IL-17 family, and is known as CTLA8 in the mouse. It is produced by T lym-phocytes and NK cells and has proinflammatory roles, inducing cytokine and chemokine production. However, its role in tumor biology remains controversial. We investigated the effects of locally produced IL-17A by transferring the gene encoding it into CT26 colon cancer cells, either in a secretory or a membrane-bound form. Expression of the membrane-bound form on CT26 cells dramatically enhanced their proliferation in vitro. The enhanced growth was shown to be due to an increased rate of cell cycle progression: after synchronizing cells by adding and withdrawing colcemid, the rate of cell cycle progression in the cells expressing the membrane-bound form of IL-17A was much faster than that of the control cells. Both secretory and membrane-bound IL-17A induced the expression of Sca-1 in the cancer cells. When tumor clones were grafted into syngeneic BALB/c mice, the tumor clones expressing the membrane-bound form IL-17A grew rapidly; those expressing the secretory form also grew faster than the wild type CT26 cells, but slower than the clones expressing the membrane-bound form. These results indicate that IL-17A promotes tumorigenicity by enhancing cell cycle progression. This finding should be considered in treating tumors and immune-related diseases.
Cell-Based IL-15:IL-15Rα Secreting Vaccine as an Effective Therapy for CT26 Colon Cancer in Mice
Thi, Van Anh Do,Jeon, Hyung Min,Park, Sang Min,Lee, Hayyoung,Kim, Young Sang Korean Society for Molecular and Cellular Biology 2019 Molecules and cells Vol.42 No.12
Interleukin (IL)-15 is an essential immune-modulator with high potential for use in cancer treatment. Natural IL-15 has a low biological potency because of its short half-life and difficulties in mass-production. IL-15Rα, a member of the IL-15 receptor complex, is famous for its high affinity to IL-15 and its ability to lengthen the half-life of IL-15. We have double-transfected IL-15 and its truncated receptor IL-15Rα into CT26 colon cancer cells to target them for intracellular assembly. The secreted IL-15:IL-15Rα complexes were confirmed in ELISA and Co-IP experiments. IL-15:IL-15Rα secreting clones showed a higher anti-tumor effect than IL-15 secreting clones. Furthermore, we also evaluated the vaccine and therapeutic efficacy of the whole cancer-cell vaccine using mitomycin C (MMC)-treated IL-15:IL-15Rα secreting CT26 clones. Three sets of experiments were evaluated; (1) therapeutics, (2) vaccination, and (3) long-term protection. Wild-type CT26-bearing mice treated with a single dose of MMC-inactivated secreted IL-15:IL-15Rα clones prolonged survival compared to the control group. Survival of MMC-inactivated IL-15:IL-15Rα clone-vaccinated mice (without any further adjuvant) exceeded up to 100%. This protection effect even lasted for at least three months after the immunization. Secreted IL-15:IL-15Rα clones challenging trigger anti-tumor response via CD4<SUP>+</SUP> T, CD8<SUP>+</SUP> T, and natural killer (NK) cell-dependent cytotoxicity. Our result suggested that cell-based vaccine secreting IL-15:IL-15Rα, may offer the new tools for immunotherapy to treat cancer.
Do Thi, Van Anh,Park, Sang Min,Lee, Hayyoung,Kim, Young Sang 한국조명·전기설비학회 2018 한국조명·전기설비학회 학술대회논문집 Vol. No.
<P>IL-9 is a known T cell growth factor with pleiotropic immunological functions, especially in parasite infection and colitis. However, its role in tumor growth is controversial. In this study, we generated tumor clones expressing the membrane-bound form of IL-9 (MB-IL-9) and investigated their influences on immune system. MB-IL-9 tumor clones showed reduced tumorigenicity but shortened survival accompanied with severe body weight loss in mice. MB-IL-9 expression on tumor cells had no effect on cell proliferation or major histocompatibility complex class I expression <I>in vitro</I>. MB-IL-9 tumor clones were effective in amplifying CD4<SUP>+</SUP> and CD8<SUP>+</SUP> T cells and increasing cytotoxic activity against CT26 cells <I>in vivo</I>. We also observed a prominent reduction in body weights and survival period of mice injected intraperitoneally with MB-IL-9 clones compared with control groups. Ratios of IL-17 to interferon (IFN)-γ in serum level and tumor mass were higher in mice implanted with MB-IL-9 tumor clones than those observed in mice implanted with control cells. These results indicate that the ectopic expression of the MB-IL-9 on tumor cells exerts an immune-stimulatory effect with toxicity. To exploit its benefits as a tumor vaccine, a strategy to control the toxicity of MB-IL-9 tumor clones should be developed.</P>
맹옥희,김용찬,김영상,백상기,이혜영 충남대학교 생물공학연구소 2002 생물공학연구지 Vol.8 No.2
Nitric oxide (NO) and NO synthases have become an important research topic in cellular and molecular biology. NO is produced by many mammalian cells and performs a broad spectrum of signaling functions in the immunological, neurological and vascular system. NO has multiple molecular targets. It can not only directly influence the activity of transcription factors but also modulate upstream signaling cascades as well as the processing of the primary gene products. It was hypothesized that NO production induced a specific set of henetic programs that might serve to alter cellular metabolism in macrophage. A technique called suppression subtractive hybridization (SSH) was adopted to identify genes differentially expressed in NO-stimulated cells.
Inhibitory effect of a phosphatidyl ethanolamine derivative on LPS-induced sepsis
Lee, Chunghyun,An, Hyun-Jung,Kim, Jung-ln,Lee, Hayyoung,Paik, Sang-Gi Springer-Verlag 2009 Molecules and cells Vol.27 No.2
<P>Sepsis is the leading cause of death in critically ill patients. Today, around 60% of all cases of sepsis are caused by Gram-negative bacteria. The cell wall component lipopoly-saccharide (LPS) is the main initiator of the cascade of cellular reactions in Gram-negative infections. The core receptors for LPS are toll-like receptor 4 (TLR4), MD-2 and CD14. Attempts have been made to antagonize the toxic effect of endotoxin using monoclonal antibodies against CD14 and synthetic lipopolysaccharides but there is as yet no effective treatment for septic syndrome. Here, we describe an inhibitory effect of a phosphatidylethanolamine derivative, PE-DTPA (phosphatidylethanolamine diethyl-enetriaminepentaacetate) on LPS recognition. PE-DTPA bound strongly to CD14 (K ( d ), 9.52 x 10(-8) M). It dose dependency inhibited LPS-mediated activation of human myeloid cells, mouse macrophage cells and human whole blood as measured by the production of tumor necrosis factor-a (TNF-alpha) and nitric oxide, whereas other phospho-lipids including phosphatidylserine and phosphatidylethanolamine had little effect. PE-DTPA also inhibited transcription dependent on NF-kappaB activation when it was added together with LPS, and it rescued LPS-primed mice from septic death. These results suggest that PE-DTPA is a potent antagonist of LPS, and that it acts by competing for binding to CD14.</P>