关键词： 活化转录因子3   活化转录因子4   核因子相关因子2   慢性阻塞性肺疾病  

摘要： 氧化/抗氧化失衡是慢性阻塞性肺疾病主要发病机制之一.转录因子转录激活因子3/转录激活因子4在氧化应激条件下能与核因子相关因子-2相互作用,调节抗氧化酶的表达,进一步探讨其在氧化应激中的表达、作用及机制将为慢性阻塞性肺疾病的防治提供新的理论依据.

摘要： Most people with type 2 diabetes (T2D) have reduced beta-cell mass, and apoptosis is a key factor for this reduction. Previously, we showed that ATF3, an adaptive-response gene, is induced by various stress signals relevant to T2D, such as high glucose and high fatty acid. Because ATF3 is proapoptotic in beta-cells, we tested the hypothesis that ATF3 plays a detrimental role and contributes to the development of T2D. We compared wild-type (WT) and ATF3 knockout (KO) mice in an animal model for T2D, high-fat diet-induced diabetes. We also used INS-1 beta-cells and primary islets to analyze the roles of ATF3 in beta-cell function, including insulin gene expression and glucose-induced insulin secretion. Surprisingly, WT mice performed better in glucose tolerance test than KO mice, suggesting a protective, rather than detrimental, role of ATF3. At 12 wk on high-fat diet, no beta-cell apoptosis was observed, and the WT and KO mice had comparable beta-cell areas. However, ATF3 deficiency significantly reduced serum insulin levels in the KO mice without affecting insulin sensitivity, suggesting reduced beta-cell function in the KO mice. Analyses using INS-1 cells and primary islets support the notion that this defect is due, at least partly, to reduced insulin gene transcription in the KO islets without detectable reduction in glucose-induced calcium influx, a critical step for insulin secretion. In conclusion, our results support a model in which, before apoptosis becomes obvious, expression of ATF3 can be beneficial by helping beta-cells to cope with higher metabolic demand. (Molecular Endocrinology 24: 1423-1433, 2010)

关键词： ATF3   Cell death   Inflammation   Islet transplantation   Primary non-function   Stress response   Transcription factor  

摘要： Islet transplantation is a potential therapeutic option for type 1 diabetes. However, the need for multiple donors per patient and heavy immunosuppression of the recipients limit its use. The goal of this study was to test whether the gene encoding activating transcription factor 3 (ATF3), a stress-inducible pro-apoptotic gene, plays a role in graft rejection in islet transplantation. We compared wild-type (WT) and Atf3 knockout (KO) islets in vitro using stress paradigms relevant to islet transplantation: isolation, inflammation and hypoxia. We also compared the WT and KO islets in vivo using a syngeneic mouse transplantation model. ATF3 was induced in all three stress paradigms and played a deleterious role in islet survival, as evidenced by the lower viability of WT islets compared with KO islets. ATF3 upregulated various downstream target genes in a stress-dependent manner. These target genes can be classified into two functional groups: (1) apoptosis (Noxa [also known as Pmaip1] and Bnip3), and (2) immunomodulation (Tnf alpha [also known as Tnf], Il-1 beta [also known as Il1b], Il-6 [also known as Il6] and Ccl2 [also known as Mcp-1]). In vivo, Atf3 KO islets performed better than WT islets after transplantation, as evidenced by better glucose homeostasis in the recipients and the reduction of the following variables in the KO grafts: caspase 3 activation, macrophage infiltration and expression of the above apoptotic and immunomodulatory genes. ATF3 plays a role in islet graft rejection by contributing to islet cell death and inflammatory responses at the graft sites. Silencing the ATF3 gene may provide therapeutic benefits in islet transplantation.

摘要： Activating transcription factor 3 (ATF3) is a basic leucine zipper transcription factor that plays a regulatory role in inflammation, cell division, and apoptosis. Mast cells (MCs) initiate many inflammatory responses and have a central role in allergy and allergic diseases. We report here that ATF3 has a central role in MC development and function. Bone marrow derived MC populations from ATF3-deficient mice are unresponsive to interleukin-3 (IL-3)-induced maturation signals, and this correlates with increased apoptosis, diminished activation of the Akt kinase, and decreased phosphorylation of the proapoptotic protein Bad. Furthermore, ATF3-null mice lacked MCs in the peritoneum and dermis, showing that the in vitro results are recapitulated in vivo. ATF3-null MCs also showed functional defects;high-affinity immunoglobulin E receptor-mediated degranulation was significantly inhibited, whereas IL-4 and IL-6 expression was enhanced. This dual role of ATF3 provides insight into the complex interplay between MC development and its subsequent physiologic role. (Blood. 2010;115(23):4734-4741)

关键词： ATF3   infraorbital nerve injury   macrophage invasion   neuropathic pain   P2X(4) receptor   serotonin selective reuptake inhibitor  

摘要： We investigated the P2X(4) receptor (P2X(4)R) expression in the cervical spinal cord, trigeminal ganglion, and infraorbital nerve (ION), after a chronic constriction injury of unilateral ION and a treatment with selective serotonin reuptake inhibitor (SSRI). A recent study has showed that SSRI inhibits P2X(4)R expression. Injured rats had significantly lower pain thresholds. In injured and slightly injured ION, the P2X(4)R expression was significantly higher than in the naive-rat ION. Injured animals with SSRI showed significantly higher pain thresholds than injured animals without the drug. Nonetheless, P2X(4)R expression in the ipsilateral ION remained high. Immunostaining showed that macrophages are the source of P2X(4)R. Our results suggest that the expression of P2X(4)R in our model is modulated not by neuropathic pain, but by slight nerve injury. NeuroReport 21:559-563 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

关键词： Far-Infrared   Radiation   Human   Cancer   Cell   Lines   G2/M   Arrest   Hypertrophy   ATF3  

摘要： Far-infrared ray (FIR) is electromagnetic wave between 4 and 1000 μm. FIR causes heating, but how it affects cells is not well understood. In this study, we developed a culture incubator that can continuously irradiate cells with FIR and examined the effects of FIR on five human cancer cell lines, namely A431 (vulva), A549 (lung), HSC3 (tongue), MCF7 (breast) and Sa3 (gingiva). We found that FIR inhibits cell proliferation and induces cell hypertrophy without apoptosis in A549, HSC3 and Sa3 cells. Flow cytometry revealed that the inhibition of proliferation was due to G2/M arrest. Contrary, FIR did not inhibit cell proliferation and cause cell hypertrophy in A431 or MCF7 cells. Microarray analysis revealed that FIR suppressed the expression of cell proliferation-related and stress-responsive genes in FIR-sensitive cell lines (A549, HSC3 and Sa3). ATF3 in particular was identified as a key mediator of the FIR effect. Over-expression of ATF3 inhibited cell proliferation and knockdown of ATF3 mRNA using an antisense oligonucleotide suppressed FIR-induced growth arrest. These results indicate that a body temperature range of FIR radiation suppresses the proliferation of A549, HSC3, Sa3 cells and it appears that ATF3 play important roles in this effect.

摘要： A variety of stress stimuli, including ischemia-reperfusion (I/R) injury, induce the transcriptional repressor ATF3 in the kidney. The functional consequences of this upregulation in ATF3 after renal I/R injury are not well understood. Here, we found that ATF3-deficient mice had higher renal I/R-induced mortality, kidney dysfunction, inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin), and apoptosis compared with wild-type mice. Furthermore, gene transfer of ATF3 to the kidney rescued the renal I/R-induced injuries in the ATF3-deficient mice. Molecular and biochemical analysis revealed that ATF3 interacted directly with histone deacetylase 1 (HDAC1) and recruited HDAC1 into the ATF/NF-kappa B sites in the IL-6 and IL-12b gene promoters. The ATF3-associated HDAC1 deacetylated histones, which resulted in the condensation of chromatin structure, interference of NF-kappa B binding, and inhibition of inflammatory gene transcription after I/R injury. Taken together, these data demonstrate epigenetic regulation mediated by the stress-inducible gene ATF3 after renal I/R injury and suggest potential targeted approaches for acute kidney injury.

关键词： Cytokines   Immunology/Innate Immunity   Immunology/Toll Receptors   Receptors/Toll-like   Signal Transduction   Transcription/Regulation   Tyrosine Kinase  

摘要： Interferon regulatory factors (IRFs) are crucial for transcription during innate immune responses. We have previously shown that the tyrosine kinase c-Src enhances IRF-3-dependent transcription in response to viral double-stranded RNA. In this study, we show that c-Src has distinct roles in Toll-like receptor (TLR)-mediated activation of IRF-5 and IRF-3. Surprisingly, c-Src inhibition markedly enhanced IRF-5 activation after treatment with unmethylated CpG, while suppressing IRF-3 activation. Also, CpG-elicited interleukin-6 mRNA production was increased, whereas IP10 mRNA synthesis was reduced in cells deficient in c-Src. Interestingly, c-Src regulated TLR-stimulated induction of activating transcription factor 3 (ATF3), a transcriptional repressor. Depletion of ATF3 by small interfering RNA markedly enhanced interleukin-6 production after CpG treatment, whereas IP10 production was reduced. These results demonstrate functional specificity for c-Src in TLR-stimulated responses and suggest that c-Src modulation and ATF3 activity may contribute to differential regulation of IRF-3-versus IRF-5-mediated gene expression.