The TH17 lineage is a novel CD4+ T cell effector subset that plays a key role in inflammatory and autoimmune responses, via its ability to produce IL-17 and IL-21. Given the potentially deleterious effects of TH17 cells, their generation needs to be strictly controlled. The regulatory pathways that prevent the inappropriate development of TH17 cells have not been fully elucidated. IRF-4 is a transcription factor that has recently emerged as a key regulator of TH17 differentiation. Our laboratory has isolated a protein, which interacts with IRF-4, that we have termed IBP (IRF-4 Binding Protein). Our studies previously demonstrated that IBP can act as an activator of Rho GTPases and that mice deficient in IBP develop a lupus-like syndrome upon aging. Here we show that TCR transgenic IBP deficient mice rapidly develop rheumatoid arthritis-like joint disease and large-vessel vasculitis. The pathology observed in the absence of IBP is associated with an enhanced responsiveness of T cells to low-levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. Furthermore, we demonstrate that the effect of IBP on cytokine production is due to its ability to sequester IRF-4 and prevent it from targeting the transcriptional regulatory regions of the IL-17 and IL-21 genes. Consistent with this finding, the enhanced ability of IBP deficient T cells to produce IL-17 and IL-21 is abolished by the concurrent lack of IRF-4. Taken together these studies suggest that IBP plays a key regulatory role in the prevention of T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.
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.
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. © 2003 Wiley-Liss, Inc. Key words: cyclooxygenase-2; renal cell carcinoma; COX-2 inhibitor; antisense DNA; tumorigenesisCarcinogenesis is a multistep process involving complicated changes of proto-oncogenes and anti-oncogenes. Studies on cancer chemoprevention have led to remarkable insights into the molecular mechanisms of cancers. Carcinogenesis in humans has been shown to be inhibited by non-steroidal anti-inflammatory drugs (NSAID). 1-3 The suppression of prostaglandin (PG) biosynthesis via inhibition of the corresponding cyclooxygenase (COX) by NSAID is thought to be the main molecular mechanism for their antineoplasia effect. 4 Such data have prompted the examination of expression of COX in human cancer tissues. Two different isoforms of COX catalyze the synthesis of PG from arachidonic acid. COX-1 is constitutively expressed in most tissues, at a relatively stable level, and it exerts diverse homeostatic functions, such as protecting the gastrointestinal tract from injury and regulating renal blood flow. COX-2 is an inducible cyclooxygenase. It is not expressed in appreciable amounts by most normal tissues but can be induced by mitogenic stimuli, growth factors, cytokines, and carcinogens. 5 COX-2 is thought to synthesize the excessive amount of PG associated with pain and fever. Studies have demonstrated upregulation ...
Hema-kinesis will evaluate whether ticagrelor monotherapy or ticagrelor combined with aspirin as compared with aspirin monotherapy can reduce blood viscosity-dependent blood flow in the feet of type 2 diabetes patients with LEAD. Eligible study participants will be randomized into a three-arm double-dummy crossover trial design. All subjects will have baseline blood viscosity measurements and determinations of microvascular flow using laser Doppler flowmetry. If the results of Hema-kinesis are positive, ticagrelor should be considered as treatment to reduce microvascular complications of LEAD in patients with type 2 diabetes.
Aim : To establish and characterize a murine xenograft model of human urothelial cancer in severe combined immunodeficient (SCID) mice for therapeutic simulation. Methods : 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. Results : 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. Conclusions : 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.