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Lingling Qiu, Teng Ma, Guobin Chang, Xiangping Liu, Xiaomin Guo, Lu Xu, Yang Zhang, Wenming Zhao, Qi Xu, Guohong Chen
NLRC5, a protein belonging to the NOD-like receptor protein family (NLRs), is highly expressed in immune tissues and cells. NLRC5 plays an important role in the immune response of humans, where its regulatory mechanism has been elucidated. However, the function and regulation of NLRC5 in chickens remains unclear. In this study, temporal expression characteristics of NLRC5 and associated genes in the STAT1 pathway in chickens following infection with Salmonellapullorum were investigated using quantitative real-time polymerase chain reaction and hierarchical cluster analyses...
October 20, 2016: Gene
Fadia J A Gujam, Donald C McMillan, Joanne Edwards
The aim of the present study was to examine the relationship between tumour cell expression of total and phosphorylated STAT1 (ph-STAT1) and STAT3 (ph-STAT-3), components of tumour microenvironment and survival in patients with invasive ductal breast cancer.Immunohistochemical analysis of total and ph-STAT1, and STAT3 were performed on tissue microarray of 384 breast cancer specimens. Tumour cell expression of STAT1 and STAT3 at both cytoplasmic and nuclear locations were combined and identified as STAT1/STAT3 tumour cell expression...
October 18, 2016: Oncotarget
Hiroko Mataki, Naohiko Seki, Keiko Mizuno, Nijiro Nohata, Kazuto Kamikawaji, Tomohiro Kumamoto, Keiichi Koshizuka, Yusuke Goto, Hiromasa Inoue
Patients with lung adenocarcinoma may benefit from recently developed molecular targeted therapies. However, analogous advanced treatments are not available for patients with lung squamous cell carcinoma (lung SCC). The survival rate of patients with the advanced stage of lung SCC remains poor. Exploration of novel lung SCC oncogenic pathways might lead to new treatment protocols for the disease. Based on this concept, we have identified microRNA- (miRNA) mediated oncogenic pathways in lung SCC. It is well known that miR-145-5p (the guide strand) functions as a tumor suppressor in several types of cancer...
September 27, 2016: Oncotarget
Lis N Velásquez, M Ayelén Milillo, M Victoria Delpino, Aldana Trotta, Pablo Fernández, Roberto G Pozner, Roland Lang, Luciana Balboa, Guillermo H Giambartolomei, Paula Barrionuevo
Brucella abortus is an intracellular pathogen capable of surviving inside of macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4(+) T cell responses that it elicits. Previously, we demonstrated that B. abortus inhibits the IFN-γ-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby B...
October 20, 2016: Journal of Leukocyte Biology
James P Strassner, John E Harris
Vitiligo is an autoimmune disease of the skin that leads to life-altering depigmentation and remains difficult to treat. However, clinical observations and translational studies over 30-40 years have led to the development of an insightful working model of disease pathogenesis: Genetic risk spanning both immune and melanocyte functions is pushed over a threshold by known and suspected environmental factors to initiate autoimmune T cell-mediated killing of melanocytes. While under cellular stress, melanocytes appear to signal innate immunity to activate T cells...
October 17, 2016: Current Opinion in Immunology
Ruijie Liu, Hadi Khalil, Suh-Chin J Lin, Michelle A Sargent, Allen J York, Jeffery D Molkentin
Nemo-like kinase (NLK) is an evolutionary conserved serine/threonine protein kinase implicated in development, proliferation and apoptosis regulation. Here we identified NLK as a gene product induced in the hearts of mice subjected to pressure overload or myocardial infarction injury, suggesting a potential regulatory role with pathological stimulation to this organ. To examine the potential functional consequences of increased NLK levels, cardiac-specific transgenic mice with inducible expression of this gene product were generated, as well as cardiac-specific Nlk gene-deleted mice...
2016: PloS One
Benjamin Y Owusu, Lidija Klampfer
The luciferase (LUC) reporter assay is commonly used to study gene expression at the transcriptional level. It is convenient, fast, sensitive, inexpensive, and provides quantitative data about small changes in transcription. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that plays a crucial role in signaling by interferons (IFNs). Here, we describe LUC reporter studies that address the role of histone deacetylase (HDAC) activity in STAT1-dependent gene activation. These experiments include overexpression of HDAC1, HDAC2, HDAC3, and HDAC4 as well as silencing of HDAC1, HDAC2, and HDAC3 through RNA interference in mammalian cancer cells...
2017: Methods in Molecular Biology
Lily Dara, Zhang-Xu Liu, Neil Kaplowitz
Hepatocyte death, which can be apoptosis or necrosis depending on the context, is a prominent feature of liver disease. The lectin concanavalin A (ConA) activates immune cells, resulting in inflammatory liver injury and hepatocyte necrosis. In this issue of the JCI, Günther et al. demonstrate that the pseudokinase mixed lineage kinase domain-like protein (MLKL) participates in hepatocyte death in ConA injury and that MLKL-mediated death is independent of the receptor-interacting protein kinase RIPK3. RIPK3 was absent in hepatocytes, and MLKL-deficient mice, but not RIPK3-deficient mice, were protected from ConA-induced liver injury...
October 17, 2016: Journal of Clinical Investigation
Xingwei Jiang, Tingting Zhou, Yan Xiao, Jiahui Yu, Shuaijie Dou, Guojiang Chen, Renxi Wang, He Xiao, Chunmei Hou, Wei Wang, Qingzhu Shi, Jiannan Feng, Yuanfang Ma, Beifen Shen, Yan Li, Gencheng Han
T cell Ig mucin-3 (Tim-3), an immune checkpoint inhibitor, shows therapeutic potential. However, the molecular mechanism by which Tim-3 regulates immune responses remains to be determined. In particular, very little is known about how Tim-3 works in innate immune cells. Here, we demonstrated that Tim-3 is involved in the development of tumor-promoting M2 macrophages in colon cancer. Manipulation of the Tim-3 pathway significantly affected the polarization status of intestinal macrophages and the progression of colon cancer...
2016: Oncoimmunology
Eva Maria Putz, Andrea Majoros, Dagmar Gotthardt, Michaela Prchal-Murphy, Eva Maria Zebedin-Brandl, Daniela Alexandra Fux, Andreas Schlattl, Robert D Schreiber, Sebastian Carotta, Mathias Müller, Christopher Gerner, Thomas Decker, Veronika Sexl
STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here, we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing a Stat1-Y701F mutant. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity as verified by RNA-seq analysis...
2016: Oncoimmunology
Claudia Günther, Gui-Wei He, Andreas E Kremer, James M Murphy, Emma J Petrie, Kerstin Amann, Peter Vandenabeele, Andreas Linkermann, Christopher Poremba, Ulrike Schleicher, Christin Dewitz, Stefan Krautwald, Markus F Neurath, Christoph Becker, Stefan Wirtz
Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor-interacting protein (RIP) kinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis...
October 18, 2016: Journal of Clinical Investigation
Zhenpeng Song, Bingrui Xiong, Hua Zheng, Anne Manyande, Xuehai Guan, Fei Cao, Lifang Ren, Yaqun Zhou, Dawei Ye, Yuke Tian
Major histocompatibility class II (MHC II)-specific activation of CD4(+) T helper cells generates specific and persistent adaptive immunity against tumors. Emerging evidence demonstrates that MHC II is also involved in basic pain perception; however, little is known regarding its role in the development of cancer-induced bone pain (CIBP). In this study, we demonstrate that MHC II expression was markedly induced on the spinal microglia of CIBP rats in response to STAT1 phosphorylation. Mechanical allodynia was ameliorated by either pharmacological or genetic inhibition of MHC II upregulation, which was also attenuated by the inhibition of pSTAT1 and pERK but was deteriorated by intrathecal injection of IFNγ...
October 11, 2016: Brain, Behavior, and Immunity
Radhika Patnala, Thiruma V Arumugam, Neelima Gupta, S Thameem Dheen
Cerebral ischemia leads to neuroinflammation and activation of microglia which further contribute to stroke pathology. Understanding regulation of microglial activation will aid in the development of therapeutic strategies that mitigate microglia-mediated neurotoxicity in neuropathologies, including ischemia. In this study, we investigated the epigenetic regulation of microglial activation by studying histone modification histone 3-lysine 9-acetylation (H3K9ac) and its regulation by histone deacetylase (HDAC) inhibitors...
October 8, 2016: Molecular Neurobiology
Murali Ganesan, Larisa Y Poluektova, Dean J Tuma, Kusum K Kharbanda, Natalia A Osna
BACKGROUND: Alcohol consumption exacerbates the pathogenesis of hepatitis C virus (HCV) infection and worsens disease outcomes. The exact reasons are not clear yet, but they might be partially attributed to the ability of alcohol to further suppress the innate immunity. Innate immunity is known to be already decreased by HCV in liver cells. METHODS: In this study, we aimed to explore the mechanisms of how alcohol metabolism dysregulates IFNα signaling (STAT1 phosphorylation) in HCV(+) hepatoma cells...
September 26, 2016: Alcoholism, Clinical and Experimental Research
Jidong Chen, Xiaolei Cui, Zhengjiang Qian, Yanjiao Li, Kang Kang, Junle Qu, Li Li, Deming Gou
BACKGROUND: Pulmonary arterial hypertension (PAH) is a lethal disease with pronounced narrowing of pulmonary vessels due to abnormal cell proliferation. The platelet-derived growth factor BB (PDGF-BB) is well known as a potent mitogen for smooth muscle cell proliferation. To better understand how this growth factor regulates pulmonary arterial smooth muscle cells (PASMCs) proliferation, we sought to characterize the response to PDGF-BB stimulation at system-wide levels, including the transcriptome and proteome...
October 6, 2016: BMC Genomics
Kristine C Olson, Paige M Kulling, Thomas L Olson, Su-Fern Tan, Rebecca J Rainbow, David J Feith, Thomas P Loughran
Large granular lymphocyte leukemia (LGLL) is a rare incurable chronic disease typically characterized by clonal expansion of CD3+ cytotoxic T-cells. Two signal transducer and activator of transcription factors, STAT1 and STAT3, are constitutively active in T-LGLL. Disruption of this activation induces apoptosis in T-LGLL cells. Therefore, considerable efforts are focused on developing treatments that inhibit STAT activation. Calcitriol, the active form of vitamin D, has been shown to decrease STAT1 and STAT3 phosphorylation in cancer cell lines and autoimmune disease mouse models...
October 7, 2016: Cancer Biology & Therapy
Chuan He Yang, Yinan Wang, Michelle Sims, Chun Cai, Ping He, Junming Yue, Jinjun Cheng, Frederick A Boop, Susan R Pfeffer, Lawrence M Pfeffer
MicroRNAs (miRNAs) play critical roles in regulating cancer cell proliferation, migration, survival and sensitivity to chemotherapy. The potential application of using miRNAs for cancer prognosis holds great promise but miRNAs with predictive value remain to be identified and underlying mechanisms of how they promote or suppress tumorigenesis are not completely understood. Here, we show a strong correlation between miR203 expression and brain cancer patient survival. Low miR203 expression is found in subsets of brain cancer patients, especially glioblastoma...
October 2, 2016: Oncotarget
Xin Xu, Kunkun Han, Jingyu Zhu, Hongwu Mao, Xu Lin, Zubin Zhang, Biyin Cao, Yuanying Zeng, Xinliang Mao
The activated JAK2-STAT3 signaling pathway is a high risk factor for multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, SC09, a potential inhibitor of cholesterol absorption, was identified in a STAT3-targeted drug screen. SC09 suppressed the activation of STAT3 in a time-course and concentration-dependent manner but did not affect its family members STAT1 and STAT5. SC09 inhibited STAT3 transcriptional activity and downregulated the expression of STAT3-regulated genes. Further studies showed that SC09 selectively inhibited JAK2 activation but not other kinases including c-Src, ERK, p38 and mTOR that are all associated with STAT3 activation...
September 26, 2016: Oncotarget
Yang Sun, Zhijian Sang, Qian Jiang, Xiaojun Ding, Youcheng Yu
Oral squamous cell carcinoma (OSCC) is a highly prevalent cancer worldwide, and OSCC often goes undiagnosed until advanced disease is present, which contributes to a low survival rate for OSCC patients. The identification of biomarkers for the early detection OSCC and novel therapeutic targets for OSCC treatment is an important research objective. We performed bioinformatics analyses of the gene expression profile of OSCC using microarray data to identify genes that contribute to the development of OSCC. We also predicted the transcription factors involved in the regulation of differential gene expression in OSCC...
October 4, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Chang He, Cheng-Rong Yu, Mary J Mattapallil, Lin Sun, Joseph Larkin Iii, Charles E Egwuagu
Uveitis is a potentially sight-threatening disease characterized by repeated cycles of remission and recurrent inflammation. The JAK/STAT pathway regulates the differentiation of pathogenic Th1 and Th17 cells that mediate uveitis. A SOCS1 mimetic peptide (SOCS1-KIR) that inhibits JAK2/STAT1 pathways has recently been shown to suppress experimental autoimmune uveitis (EAU). However, it is not clear whether SOCS1-KIR ameliorated uveitis by targeting JAK/STAT pathways of pathogenic lymphocytes or via inhibition of macrophages and antigen-presenting cells that also enter the retina during EAU...
2016: Mediators of Inflammation
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