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T cell regulators

Adam C Labonte, Sun-Sang J Sung, Lucas T Jennelle, Aditya P Dandekar, Young S Hahn
: The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis and hepatocellular carcinoma. Macrophages (Mϕ) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mϕ in limiting hepatic inflammation or resolving liver damage have not been fully understood...
October 22, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Lin Fu, Jinlong Shi, Anqi Liu, Lei Zhou, Mengmeng Jiang, Huaping Fu, Keman Xu, Dandan Li, Ailing Deng, Qingyi Zhang, Yifan Pang, Yujie Guo, Kai Hu, Jiansuo Zhou, Yapeng Wang, Wenrong Huang, Yu Jing, Liping Dou, Lili Wang, Kailin Xu, Xiaoyan Ke, Clara Nervi, Yonghui Li, Li Yu
MicroRNA-9-1(miR-9-1) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that miR-9-1 is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying miR-9-1 down-regulation and the RUNX1-RUNX1T1 fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. RUNX1-RUNX1T1 can induce leukemogenesis through resides in and functions as a stable RUNX1-RUNX1T1-containing transcription factor complex...
October 22, 2016: International Journal of Cancer. Journal International du Cancer
Man Liu, Jingying Zhou, Zhiwei Chen, Alfred Sze-Lok Cheng
The tumour microenvironment plays an instrumental role in cancer development, progression and treatment response/resistance. Accumulating evidence underscores the fundamental importance of epigenetic regulation in tumour immune evasion. Following many pioneering discoveries demonstrating malignant transformation through epigenetic anomalies ("epimutations"), there is also growing emphasis on elucidating aberrant epigenetic mechanisms that reprogramme the milieu of tumour-associated immune and stromal cells toward an immunosuppressive state...
October 22, 2016: Journal of Pathology
Junsik Park, Minsuk Kwon, Eui-Cheol Shin
During immune responses antigen-specific T cells are regulated by several mechanisms, including through inhibitory receptors and regulatory T cells, to avoid excessive or persistent immune responses. These regulatory mechanisms, which are called 'immune checkpoints', suppress T cell responses, particularly in patients with chronic viral infections and cancer where viral antigens or tumor antigens persist for a long time and contribute to T cell exhaustion. Among these regulatory mechanisms, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) are the most well-known receptors and both have been targeted for drug development...
October 21, 2016: Archives of Pharmacal Research
Xiaodan Luo, Lihua Xu, Yangqiu Li, Huo Tan
Graft-versus-host disease (GVHD) induced by host antigen-presenting cells (APCs) and donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). Notch signaling pathway is a highly conserved cell-cell communication that is important in T cell development. Recently, Notch signaling pathway is reported to be involved in regulating GVHD. To investigate the role of Notch inhibition in modulating GVHD, we established MHC-mismatched murine allo-BMT model. We found that inhibition of Notch signaling pathway by γ-secretase inhibitor in vivo could reduce aGVHD, which was shown by the onset time of aGVHD, body weight, clinical aGVHD scores, pathology aGVHD scores, and survival...
October 21, 2016: Cell Biology and Toxicology
Julie Grandbois, Sandhya Khurana, Kelly Graff, Phong Nguyen, Leah Meltz, T C Tai
Epinephrine is synthesized by the catecholamine biosynthetic enzyme, phenylethanolamine N-methyltransferase (PNMT), primarily in chromaffin cells of the adrenal medulla and secondarily in brainstem adrenergic neurons of the medulla oblongata. Epinephrine is an important neurotransmitter/neurohormone involved in cardiovascular regulation; however, overproduction is detrimental with negative outcomes such as cellular damage, cardiovascular dysfunction, and hypertension. Genetic mapping studies have linked elevated expression of PNMT to hypertension...
October 18, 2016: Neuroscience Letters
Liqing Wang, Suresh Kumar, Satinder Dahiya, Feng Wang, Jian Wu, Kheng Newick, Rongxiang Han, Arabinda Samanta, Ulf H Beier, Tatiana Akimova, Tricia R Bhatti, Benjamin Nicholson, Mathew P Kodrasov, Saket Agarwal, David E Sterner, Wei Gu, Joseph Weinstock, Tauseef R Butt, Steven M Albelda, Wayne W Hancock
Foxp3+ T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or "secondary" modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3...
October 15, 2016: EBioMedicine
Man Chu, Lai Shan Tam, Jing Zhu, Delong Jiao, De Hua Liu, Zhe Cai, Jie Dong, Christopher Wei Kai Lam, Chun Kwok Wong
The newly named interleukin (IL)-36 subfamily member IL-38 has been shown to exert anti-inflammatory activity. However, the in vivo immunomodulatory activity of IL-38 was poorly investigated in systemic lupus erythematosus (SLE). We have investigated the expression of CD4(+)IL-17(+) Th17, CD4(+)IFN-γ(+) Th1 and CD3(+)CD4(-)CD8(-) double negative (DN) T cells and the related immunopathological mechanisms in female MRL/lpr mice model of spontaneous lupus-like disease, with or without IL-38 treatment. Intravenous administration of murine recombinant IL-38 into MRL/lpr mice can ameliorate the lupus-like clinical symptoms including proteinuria, leukocyteuria and skin lesions...
October 17, 2016: Immunobiology
J R Teijaro
Since Isaac's and Lindenmann's seminal experiments over 50 years ago demonstrating a soluble factor generated from heat killed virus-stimulated chicken embryos could inhibit live influenza virus replication, the term interferon has been synonymous with inhibition of virus replication. While the antiviral properties of type 1 interferon (IFN-I) are undeniable, recent studies have reported expanding and somewhat unexpected roles of IFN-I signaling during both acute and persistent viral infections. IFN-I signaling can promote morbidity and mortality through induction of aberrant inflammatory responses and recruitment of inflammatory innate immune cell populations during acute respiratory viral infections...
2016: Advances in Immunology
A Ulges, E Schmitt, C Becker, T Bopp
The immune system has evolved to defend the organism against an almost infinite number of pathogens in a locally confined and antigen-specific manner while at the same time preserving tolerance to harmless antigens and self. Regulatory T (Treg) cells essentially contribute to an immunoregulatory network preventing excessive immune responses and immunopathology. There is emerging evidence that Treg cells not only operate in secondary lymphoid tissue but also regulate immune responses directly at the site of inflammation...
2016: Advances in Immunology
Greg Hodge, Eugene Roscioli, Hubertus Jersmann, Hai B Tran, Mark Holmes, Paul N Reynolds, Sandra Hodge
BACKGROUND: Corticosteroid resistance is a major barrier to effective treatment of COPD. We have shown that the resistance is associated with decreased expression of glucocorticoid receptor (GCR) by senescent CD28nullCD8+ pro-inflammatory lymphocytes in peripheral blood of COPD patients. GCR must be bound to molecular chaperones heat shock proteins (Hsp) 70 and Hsp90 to acquire a high-affinity steroid binding conformation, and traffic to the nucleus. We hypothesized a loss of Hsp70/90 from these lymphocytes may further contribute to steroid resistance in COPD...
October 21, 2016: Respiratory Research
Marco Gelpi, Hans J Hartling, Kristina Thorsteinsson, Jan Gerstoft, Henrik Ullum, Susanne D Nielsen
BACKGROUND: Symptomatic primary HIV infection is associated with an adverse prognosis, and immediate initiation of combination antiretroviral therapy (cART) is recommended. However, little is known about immunological predictors of immune recovery. Thymic Stromal Lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cells homeostatic polyclonal proliferation and regulates Th17/regulatory T-cell balance, immunological functions known to be affected during primary HIV infection. The aim of this study was to describe immune recovery in primary and chronic HIV infection and possible impact of TSLP...
October 21, 2016: BMC Infectious Diseases
Alison T Merryweather-Clarke, Alex J Tipping, Abigail A Lamikanra, Rui Fa, Basel Abu-Jamous, Hoi Pat Tsang, Lee Carpenter, Kathryn J H Robson, Asoke K Nandi, David J Roberts
BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) are a potentially invaluable resource for regenerative medicine, including the in vitro manufacture of blood products. HiPSC-derived red blood cells are an attractive therapeutic option in hematology, yet exhibit unexplained proliferation and enucleation defects that presently preclude such applications. We hypothesised that substantial differential regulation of gene expression during erythroid development accounts for these important differences between hiPSC-derived cells and those from adult or cord-blood progenitors...
October 21, 2016: BMC Genomics
Zhaoxu Li, Junzhe Zhang, Jicun Tang, Ruiying Wang
γδ T cells has been shown to exhibit profound antitumor effects in a broad range of tumor entities, including OS. However, resistance to γδ T cells is a serious problem in the management of OS. This study investigates the impact of celastrol on the expression of death receptors 4/5 (DR4/5) on OS cell lines (HOS, U2OS) and cancer cell lysis by γδ T cells. The results showed that celastrol increased transcription of DR4/5 in HOS and U2OS, leading to increased cell surface, and total DR4/5 protein expression...
October 19, 2016: Oncotarget
Yoshikane Nonagase, Kimio Yonesaka, Hisato Kawakami, Satomi Watanabe, Koji Haratani, Takayuki Takahama, Naoki Takegawa, Hiroto Ueda, Junko Tanizaki, Hidetoshi Hayashi, Takeshi Yoshida, Masayuki Takeda, Yasutaka Chiba, Takao Tamura, Kazuhiko Nakagawa, Junji Tsurutani
BACKGROUND: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. RESULTS: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel...
October 19, 2016: Oncotarget
Allegra T Aron, Morten O Loehr, Jana Bogena, Christopher J Chang
Iron is essential for sustaining life, as its ability to cycle between multiple oxidation states is critical for catalyzing chemical transformations in biological systems. However, without proper regulation, this same redox capacity can trigger oxidative stress events that contribute to aging along with diseases ranging from cancer to cardiovascular and neurodegenerative disorders. Despite its importance, methods for monitoring biological iron bound weakly to cellular ligands-the labile iron pool-to generate a response that preserves spatial and temporal information remain limited, owing to the potent fluorescence quenching ability of iron...
October 21, 2016: Journal of the American Chemical Society
Bradley P Weegman, Ahmad Essawy, Peter Nash, Alexandra L Carlson, Kristin J Voltzke, Zhaohui Geng, Marjan Jahani, Benjamin B Becker, Klearchos K Papas, Meri T Firpo
In this demonstration, spheroids formed from the β-TC6 insulinoma cell line were cultured as a model of manufacturing a mammalian islet cell product to demonstrate how regulating nutrient levels can improve cell yields. In previous studies, bioreactors facilitated increased culture volumes over static cultures, but no increase in cell yields were observed. Limitations in key nutrients such as glucose, which were consumed between batch feedings, can lead to limitations in cell expansion. Large fluctuations in glucose levels were observed, despite the increase in glucose concentrations in the media...
September 25, 2016: Journal of Visualized Experiments: JoVE
Gianluigi Franci, Federica Sarno, Angela Nebbioso, Lucia Altucci
Epigenetic modifications are functionally involved in gene expression regulation. In particular, histone posttranslational modifications play a crucial role in functional chromatin organization. Several drugs able to inhibit or stimulate some families of proteins involved in epigenetic histone regulation have been found, a number of which are FDA-approved for the treatment of cutaneous T-cell lymphoma or are in phase I/II/III clinical trials for solid tumors. Although some protein families, such as histone deacetylases and their inhibitors, are well characterized, our understanding of histone lysine demethylases is still incomplete...
October 21, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Rui-Li Zhang, Jun-Ping Yang, Li-Xia Peng, Li-Sheng Zheng, Ping Xie, Meng-Yao Wang, Yun Cao, Zhi-Ling Zhang, Fang-Jian Zhou, Chao-Nan Qian, Yong-Xing Bao
Clear cell renal cell carcinoma (ccRCC) is a common pathological subtype of renal cancer. Although the recent application of molecular-targeted agents has modestly improved the prognosis of ccRCC patients, their outcome is still poor. It is therefore important to characterize the molecular and biological mechanisms responsible for the development of ccRCC. Approximately 25% ccRCC patients involves the loss of RNA-binding protein QKI at 6q26, but the role of QKI in ccRCC is unknown. Here, we found that QKI-5 was frequently downregulated in ccRCC patients and its down-regulation was significantly associated with clinical features including T status, M status, and differentiation grade, and poorer patient prognosis...
October 21, 2016: Cell Cycle
Xiu-Zhi Wu, Qiong Zhou, Hua Lin, Kan Zhai, Xiao-Juan Wang, Wei-Bing Yang, Huan-Zhong Shi
RATIONALE: Toll like receptor (TLR) 2 is well known by sensing multiple ligands; however, its role in the development of malignant pleural effusion (MPE) remains unknown. We performed the present study to explore the impact of TLR2 signaling on the development of MPE, and to define the underline mechanisms by which TLR2 works. METHODS: Development of MPE was compared between TLR2-/- and wild type (WT) mice. The effect of TLR2 on differentiation of Th17, Th9, and Th2 cells in MPE was explored...
October 21, 2016: American Journal of Respiratory Cell and Molecular Biology
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