Qinzhong Chen

Columbia University, New York City, NY, United States

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Publications (8)72.83 Total impact

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    ABSTRACT: TLRs play a fundamental role in innate immune responses. Although Rho GTPases have been implicated in TLR-mediated signaling pathways, the molecules that control their activation in response to TLR engagement are largely unknown. IFN regulatory factor-4-binding protein (IBP; which is encoded by the gene Def6) is a unique type of activator for Rac that plays a crucial role in TCR-mediated signaling and adaptive immune responses. Here, we demonstrate that IBP/Def6 also controls innate immune responses by modulating TLR-induced signaling events. Mice deficient in IBP/Def6 are protected from LPS-induced septic shock. This protection is associated with a decrease in the production of proinflammatory cytokines and is accompanied by diminished activation of MAPKs and NF-kappaB. Our results thus identify IBP/Def6 as a novel component of the TLR4-induced signaling cascade that controls the production of proinflammatory cytokines.
    Journal of leukocyte biology 01/2009; 85(3):539-43. · 4.99 Impact Factor
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    Immunity 01/2009; 31(1):2-3. · 19.80 Impact Factor
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    ABSTRACT: The T helper 17 (Th17) cell lineage is important in inflammatory and autoimmune responses, via its ability to produce interleukin-17 (IL-17) and IL-21. Given the potentially deleterious effects of Th17 cells, their generation needs to be strictly controlled. IRF-4 is a transcription factor that has recently emerged as a key regulator of Th17 cell differentiation. Here, we showed that mice deficient in a previously isolated protein, IBP (IRF-4-binding protein), rapidly developed rheumatoid arthritis-like joint disease and large-vessel vasculitis. The pathology was associated with an enhanced responsiveness of T cells to low levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. IBP sequestered IRF-4 and prevented it from targeting the transcriptional regulatory regions of the genes that encode IL-17 and IL-21. Thus, IBP appears to be important in preventing T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.
    Immunity 01/2009; 29(6):899-911. · 19.80 Impact Factor
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    ABSTRACT: IFN regulatory factor 4-binding (IRF-4-binding) protein (IBP) is a novel type of activator of Rho GTPases that is recruited to the immunological synapse upon TCR stimulation. Here we demonstrate that loss of IBP leads to the spontaneous development of a systemic autoimmune disorder characterized by the accumulation of effector/memory T cells and IgG+ B cells, profound hypergammaglobulinemia, and autoantibody production. Similar to human SLE, this syndrome primarily affects females. T cells from IBP-deficient mice are resistant to death in vitro as well as in vivo and exhibit selective defects in effector function. In the absence of IBP, T cells respond suboptimally to TCR engagement, as demonstrated by diminished ERK1/2 activation, decreased c-Fos induction, impaired immunological synapse formation, and defective actin polymerization. Transduction of IBP-deficient T cells with a WT IBP protein, but not with an IBP mutant lacking the Dbl-like domain required for Rho GTPase activation, rescues the cytoskeletal defects exhibited by these cells. Collectively, these findings indicate that IBP, a novel regulator of Rho GTPases, is required for optimal T cell effector function, lymphocyte homeostasis, and the prevention of systemic autoimmunity.
    Journal of Clinical Investigation 03/2006; 116(3):703-14. · 12.81 Impact Factor
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    ABSTRACT: To establish and characterize a murine xenograft model of human urothelial cancer in severe combined immunodeficient (SCID) mice for therapeutic simulation. Pieces of 30 freshly resected urothelial tumors (24 obtained from bladder and 6 from ureter or pelvis) were implanted subcutaneously into SCID mice, and xenograft tumors were passed in tumorigenic cases. At each passage, histopathology, TP53 mutational status assessed by yeast p53 functional assay, and the Ki-67 labeling index (LI) were examined to evaluate the preservation of original features. A growth delay assay after single-dose irradiation was performed in four representative xenografts. Tumor growth was observed in 18 mice (60%, 18/30). Histologically, 15 of the 18 were epithelial carcinomas similar to the original tumors, whereas the other 3 were Epstein-Barr virus-associated lymphoproliferative disease, resulting in a 50% (15/30) take rate. No correlation was found between the tumor take rate and the clinicopathologic features, TP53 mutational status, or Ki-67 LI of the patients' tumors. Of these 15 xenografts, 11 xenografts were passed from 3 to 10 generations. TP53 mutational status remained stable during the passages, and the Ki-67 LI of eight xenografts was within a range of 50% of the LI of the original tumors, although the other three xenografts increased by over 50%. Specific growth delay after irradiation, independent of the original tumor growth speed and Ki-67 LI, was observed in four xenografts. SCID mice are useful recipients for investigations of human urothelial cancer with a wide biological range. This easy-to-handle xenograft system can help to develop a better in vivo preclinical evaluation system for therapeutic agents as well as the investigation of tumor pathophysiology.
    International Journal of Urology 02/2006; 13(1):47-57. · 1.73 Impact Factor
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    ABSTRACT: We have previously confirmed that cyclooxygenase-2 (COX-2) is expressed in a human renal cell carcinoma (RCC) cell line and it has an important role in cell tumorigenesis and angiogenesis. In the current study we evaluated the impact on cell adhesion and tumor invasiveness in human RCC cell lines by transfection of COX-2 sense and antisense cDNAs. A human RCC cell line that expresses COX-2 was transfected with COX-2 sense or antisense cDNA. E-cadherin expression in parental cells of OS-RC-2 and transfectants was detected by real-time polymerase chain reaction and Western blotting. The expression of beta-catenin was detected by Western blotting. Zymography was used to detect gelatinase activity. CD44 expression in parental cells and transfectants was detected by fluorescence activated cell sorting. Cell adhesion was detected by adhesion assay and cell invasive ability was detected by invasion assay. E-cadherin expression was increased in antisense transfectants and decreased in sense transfectants compared with parental cells at the mRNA and protein levels. However, obvious consistent changes in beta-catenin expression could not be confirmed in parental cells and transfectants, nor were there any significant differences in gelatinase activity in parental cells and transfectants. CD44 expression was increased in sense transfectants and decreased in antisense transfectants compared with parental cells. Adhesion to hyaluronan coated wells was significantly enhanced in sense transfectants and inhibited in antisense transfectants compared with parental cells. Compared with parental cells invasive ability was significantly increased in sense transfectants and decreased in antisense transfectants. The results demonstrate that COX-2 expression has a crucial role in cell invasion ability and the suppression of COX-2 expression might regulate adhesion molecule expression and inhibit invasive ability in the RCC cell line OS-RC-2.
    The Journal of Urology 12/2004; 172(6 Pt 1):2153-7. · 3.75 Impact Factor
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    ABSTRACT: Accumulating evidences indicate that cyclooxygenase (COX)-2 plays an important role in tumorigenesis in many human cancers. Yet the relationship between COX-2 and human renal cell carcinoma (RCC) remains unclear. The aim of our study was to evaluate COX-2 expression in human RCC cell lines and its role in tumorigenesis of human RCC. Among the human RCC cell lines (SMKT-R4, OS-RC-2, ACHN) and normal renal cell line RPTEC, COX-2 overexpression was found in OS-RC-2 cells both at mRNA and protein levels. COX-2 sense- and antisense-orientated vectors were constructed and transferred into RCC cells. Significant suppression of cellular proliferation was demonstrated in OS-RC-2 antisense transfectants, whereas promotion was found in SMKT-R4 sense transfectants by colony-forming assay despite the observation that COX-2 specific inhibitor NS398 exhibited similar IC50 among RCC cell lines by MTT assay. In comparison with parent cells and sense transfectants, significant suppression of COX-2 expression and PGE2 production and increase in butyrate-induced apoptosis were observed in OS-RC-2 antisense transfectants by Western blot, ELISA assay and FACS analysis, respectively. Furthermore, tumor growth and angiogenesis of OS-RC-2 antisense transfectants in nude mice was significantly suppressed and the survival time of these mice was significantly prolonged. Our study demonstrates that COX-2 is overexpressed in OS-RC-2 RCC cell line and plays an important role in tumorigenesis of the cells in vivo, which implies that COX-2 may be a therapeutic target for COX-2-expressing RCC, and that suppression of COX-2 expression by antisense-based strategy may have potential utility in treatment of COX-2-expressing RCC.
    International Journal of Cancer 04/2004; 108(6):825-32. · 6.20 Impact Factor
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    ABSTRACT: We established the culture condition of seeding urothelial cells onto a scaffold for implantation into the peritoneal cavity and evaluated the histology of implanted urothelial cells. In part 1 of the study cultured porcine bladder urothelial cells were seeded onto 3 types of collagen gel made on microporous membrane, including collagen gel with or without cultured porcine bladder fibroblasts, or a feeder layer. The macroscopic and microscopic appearance of the gel with urothelial cells were examined in vitro. As an in vivo study, cultured porcine bladder urothelial cells were seeded onto a collagen gel/sponge matrix with or without cultured fibroblasts, or a feeder layer. Urothelial cell survival on each matrix was evaluated 28 days after implantation onto the omentum or mesentery of nude rats. In part 2 of the study rat urothelial cells were cultured and seeded onto fibrin gel/atelocollagen sponge matrix as an autologous implantation model. After 7 days of cultivation the matrix was folded with urothelial cells inside, implanted onto the mesentery and serially evaluated. Gel containing cultured fibroblasts was shrunken and basement membrane formation was observed on the gel with cultured fibroblasts or the feeder layer in vitro. Urothelial cells cultured with the feeder layer better survived on the collagen based matrix and formed a hollow-like lumen when implanted into the peritoneal cavity. The regenerated urothelium in an autologous implantation showed the same histological features as normal bladder urothelium. Selection of less degradable matrix and formation of basement membrane are critical for survival of implanted urothelial cells. The regenerated urothelium in an autologous implantation model seems to have the similar properties to the normal urothelium.
    The Journal of Urology 01/2004; 170(6 Pt 1):2480-5. · 3.75 Impact Factor