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Review : Regulation of nuclear factor-kB in autoimmunity
( Shao Cong Sun ),( Jae Hoon Chang ),( Jin Jin ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
Nuclear factor (NF)-kB transcripition factors are pivotal regulators of innate and adaptive immune responses, and perturbations of NF- kB signaling contribute to the pathogenesis of immunological disorders. NF-kB is a well-known proinflammatory mediator, and its deregu-lated activation is associated with the chronic inflamma-tion of autoimmune diseases. Paradoxically, NF-kB plays a crucial role in the establishment of immune tolerance including both central tolerance and the peripheral func-ton of regulatory T (Treg) cells. Thus, defective or deregulated activation of NF-kB may contribute to au-toimmunity and inflammation, highlighting the impor-tance of tightly controlled NF-kB signaling. This review focuses on recent progress regarding NF-kB regulation and its association with autoimmunity.
Survival and maintenance of regulatory T cells require the kinase TAK1
( Jae Hoon Chang ),( Hongbo Hu ),( Shao Cong Sun ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
Regulatory T(Treg) cells play a central role inregulating peripheral immune tolerance and preventing autoimmunity. Despite the extensive studies on the development of Treg cells, the molecular mechanisms that maintain the population of committed Trge cells remain poorly understood. We show here that Treg-conditional ablation of the kinase TAK1 reduced the number of Treg cells in the peripheral lymphoid organs, causing abnormal activation of conventional T cells and autoimmune symptoms. Using an inducible gene knockout approach, we further demonstrate that TAK1 is crucial for the survival of Treg cells. Expression of a constitutively active IκB Kinase partially restored the level of Treg cells in the TAK1Treg-Ko mice. These results suggest a crucial role TAK1 for maintaining the survival of committed treg cells under physiological conditions.
Coefficient of Restitution and Kinetic Energy Loss of Rockfall Impacts
Li-Ping Li,Shang-qu Sun,Shucai Li,Qian-qing Zhang,Cong Hu,Shao-shuai Shi 대한토목학회 2016 KSCE JOURNAL OF CIVIL ENGINEERING Vol.20 No.6
This paper presents the results of the coefficient of restitution and the kinetic energy loss rate obtained by lab experiment, two parameters that are crucial for rockfall impact. However, various definitions of coefficient of restitution exist and the most appropriate one is still not formed and obtained. In addition, the energy variation during the rockfall impacts has important significance in practical design. In this research, two kind shapes of blocks including plate and strip were adopted in the laboratory testing and the block material was tested before, indicating that the material has sufficient strength to prevent shattering during the impact. Furthermore, an apparatus specifically built for this study was established including a base, a slope and a releasing device. The falling testing was performed using plate and strip block while the falling height as well as the slope angle and releasing height were altered during the tests in order to estimate the effect of each parameter on the coefficients of restitution and energy loss rate. It was observed that collision reflection angle is less than impact angle for all, suggesting energy loss in collision. Impact angle decreases with increasing slope angle while there was no obvious effect of releasing height and releasing angle on impact angle. The relevant coefficient of restitution was found to decrease with impact angle, and the kinetic energy loss rate increased. Finally, the kinetic energy before and after the impact was found to significantly affect the COR and energy loss rate and the results can provide basis for mitigation measures.
Outd7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination
( Hongbo Hu ),( Hui Wang ),( Yichuan Xiao ),( Jin Jin ),( Jae Hoon Chang ),( Qiang Zou ),( Xiaopin Xie ),( Xuhong Cheng ),( Shao Cong Sun ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
Signal transduction from the T ceII receptor (TCR) is crucial for T cell-mediated immune responses and, when deregulated, also contributes to the development of autoimmunity. How TCR signaling is regulated is incompletely understood. In this study, we demonstrate a ubiquitin-dependent mechanism in which the deubiquitinase Otud7b has a crucial role in facilitatinq TCR signaling. Upon TCR ligation, Olud7b is rapidly recruited to the tyrosine kinase Zap70, a central mediator of TCR-proximal signaling. Otud7b deficiency attenuates the activation of Zap70 and its downstream pathways and impairs T cell activation and differentiation, rendering mice refractory to T cell-mediated autoimmune and inflammatory responses. Olud7b facilitated Zap70 activation by deubiquitinating Zap70, thus preventing the association of Zap70 with the negative-regulatory phosphatases SIs1 and Sts2. These findings establish Otud7b as a positive requlator of TCR-proximal signaling and T cell activation. highlighting the importance of deubiquitination in regulaling Zap70 function.
( Mako Nakaya ),( Yichuan Xiao ),( Xiaofei Zhou ),( Jae Hoon Chang ),( Mikyong Chang ),( Xuhong Cheng ),( Marzenna Blonska ),( Xin Lin ),( Shao Cong Sun ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.
Li, Jie,Yang, Chun-Xu,Mei, Zi-Jie,Chen, Jing,Zhang, Shi-Min,Sun, Shao-Xing,Zhou, Fu-Xiang,Zhou, Yun-Feng,Xie, Cong-Hua Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.10
Cancer patients often suffer from local tumor recurrence after radiation therapy. Cell cycling, an intricate sequence of events which guarantees high genomic fidelity, has been suggested to affect DNA damage responses and eventual radioresistant characteristics of cancer cells. Here, we established a radioresistant lung cancer cell line, A549R, by exposing the parental A549 cells to repeated ${\gamma}$-ray irradiation with a total dose of 60 Gy. The radiosensitivity of A549 and A549R was confirmed using colony formation assays. We then focused on examination of the cell cycle distribution between A549 and A549R and found that the proportion of cells in the radioresistant S phase increased, whereas that in the radiosensitive G1 phase decreased. When A549 and A549R cells were exposed to 4 Gy irradiation the total differences in cell cycle redistribution suggested that G2-M cell cycle arrest plays a predominant role in mediating radioresistance. In order to further explore the possible mechanisms behind the cell cycle related radioresistance, we examined the expression of Cdc25 proteins which orchestrate cell cycle transitions. The results showed that expression of Cdc25c increased accompanied by the decrease of Cdc25a and we proposed that the quantity of Cdc25c, rather than activated Cdc25c or Cdc25a, determines the radioresistance of cells.
The Kinase TBK1 controls lgA class switching by negatively regulating noncanonical NF-kF dignaling
( Jin Jin ),( Yichuan Xiao ),( Jae Hoon Chang ),( Jiayi Yu ),( Hongbo Hu ),( Robyn Starr ),( George C Brittain ),( Mikyoung Chang ),( Xuhong Cheng ),( Shao Cong Sun ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
Immunoglobulin class switching is crucial for the generation of antibody diversity in humoral immunity and, when deregulated, also has severe pathological consequences. How the magnitude of immunoglobulin isotype switching is controlled is still poorly understood. Here we identify thekinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype. B cell-specific ablation of TBK1 in mice resulted in uncontrolled production of IgA and the development of nephropathy-like disease signs. TBK1 negatively regulated IgA class switchingby attenuating noncanonical signaling via the transcription factor NF-κB, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase NIK. Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and identify a unique mechanism that controls IgA production.
TRAF3 regulates the effector function of regulatory T cells and humoral immune responses
( Jae Hoon Chang ),( Hongbo Hu ),( Jin Jin ),( Nahum Puebla Osorio ),( Yichuan Xiao ),( Brian E Gilbert ),( Robert Brink ),( Stephen E Ullrich ),( Shao Cong Sun ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Regulatory T cells (Treg cells) control different aspects of immune responses, but how the effector functions of Treg cells are regulated is incompletely understood. Here we identified TNF receptor-associated factor 3 (TRAF3) as a regulator of Treg cell function. Treg cell-specific ablation of TRAF3 impaired CD4 T cell homeostasis, characterized by an increase in the Th1 type of effector/memory T cells. Moreover, the ablation of TRAF3 in Treg cells resulted in increased antigen-stimulated activation of follicular T helper cells (TFH cells), coupled with heightened formation of germinal centers and production of high-affinity IgG antibodies. Although the loss of TRAF3 did not reduce the overall frequency of Treg cells, it attenuated the antigen-stimulated production of follicular Treg cells (TFR cells). TRAF3 signaling in Treg cells was required to maintain high level expression of inducible co-stimulator (ICOS), which in turn was required for TFR cell generation and inhibition of antibody responses. These findings establish TRAF3 as a mediator of Treg cell function in the regulation of antibody responses and suggest a role for TRAF3 in mediating ICOS expression in Treg cells.