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Levi Todd, Natalie Squires, Lilianna Suarez, Andy J Fischer
Müller glia are capable of de-differentiating and proliferating to become Müller glia-derived progenitor cells (MGPCs) with the ability to regenerate retinal neurons. One of the cell-signaling pathways that drives the reprogramming of Müller glia into MGPCs in the zebrafish retina is the Jak/Stat-pathway. However, nothing is known about the influence of Jak/Stat-signaling during the formation of MGPCs in the retinas of warm-blooded vertebrates. Accordingly, we examined whether Jak/Stat-signaling influences the formation of MGPCs and differentiation of progeny in the avian retina...
October 19, 2016: Scientific Reports
Franklin D Echevarria, Abigayle E Rickman, Rebecca M Sappington
OBJECTIVE: The interleukin-6 (IL-6) family of cytokines and their signal transducer glycoprotein (gp130) are implicated in inflammatory and cell survival functions in glaucoma. There are several avenues for interdependent modulation of IL-6 family members and gp130 signaling. Here we investigated whether IL-6 modulates gp130 and related neuroinflammatory, cell survival and regulatory signaling in both healthy and glaucomatous retina. METHODS: In naïve and glaucomatous (Microbead Occlusion Model), wildtype (WT) and IL-6 knockout (IL-6-/-) mice, we examined gp130 protein expression and localization, using western blot and immunohistochemistry...
August 2016: Journal of Clinical & Cellular Immunology
Yu Shi, Wenchao Zhou, Lin Cheng, Cong Chen, Zhi Huang, Xiaoguang Fang, Qiulian Wu, Zhicheng He, Senlin Xu, Justin D Lathia, Yifang Ping, Jeremy N Rich, Xiu-Wu Bian, Shideng Bao
Glioblastoma (GBM) is the most malignant and lethal brain tumor harboring glioma stem cells (GSCs) that promote tumor propagation and therapeutic resistance. GSCs preferentially express several critical cell surface molecules that regulate the pro-survival signaling for maintaining the stem cell-like phenotype. Tetraspanin CD9 has recently been reported as a GSC biomarker that is relevant to the GSC maintenance. However, the underlying molecular mechanisms of CD9 in maintaining GSC property remain elusive. Herein, we report that CD9 stabilizes the IL-6 receptor glycoprotein 130 (gp130) by preventing its ubiquitin-dependent lysosomal degradation to facilitate the STAT3 activation in GSCs...
October 14, 2016: Cell Death and Differentiation
Irini Sereti, Shelly J Krebs, Nittaya Phanuphak, James L Fletcher, Bonnie Slike, Suteeraporn Pinyakorn, Robert J O'Connell, Adam Rupert, Nicolas Chomont, Victor Valcour, Jerome H Kim, Merlin L Robb, Nelson L Michael, Daniel C Douek, Jintanat Ananworanich, Netanya S Utay
BACKGROUND:  Serious non-AIDS events cause substantial morbidity and mortality despite HIV suppression with antiretroviral therapy (ART). Biomarkers of inflammation, coagulation cascade activation, and fibrosis predict these end-organ events. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these biomarker levels. METHODS:  Plasma samples were obtained from participants starting ART during acute HIV infection, chronic HIV infection, and HIV-uninfected participants, from Bangkok, Thailand...
October 12, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Kei Matsumoto, Sandhya Xavier, Jun Chen, Yujiro Kida, Mark Lipphardt, Reina Ikeda, Annie Gevertz, Mario Caviris, Antonis K Hatzopoulos, Ivo Kalajzic, James Dutton, Brian B Ratliff, Hong Zhao, Zbygniew Darzynkiewicz, Stefan Rose-John, Michael S Goligorsky
: : Accumulation of myofibroblasts is a hallmark of renal fibrosis. A significant proportion of myofibroblasts has been reported to originate via endothelial-mesenchymal transition. We initially hypothesized that exposing myofibroblasts to the extract of endothelial progenitor cells (EPCs) could reverse this transition. Indeed, in vitro treatment of transforming growth factor-β1 (TGF-β1)-activated fibroblasts with EPC extract prevented expression of α-smooth muscle actin (α-SMA); however, it did not enhance expression of endothelial markers...
October 5, 2016: Stem Cells Translational Medicine
Carl D Richards, Laura Izakelian, Anisha Dubey, Grace Zhang, Steven Wong, Karen Kwofie, Aatif Qureshi, Fernando Botelho
IL-33 modulates both innate and adaptive immune responses at tissue sites including lung and may play critical roles in inflammatory lung disease. Although IL-33 expression can be altered upon NF-Kappa B activation, here we examine regulation by Oncostatin M, a gp130 cytokine family member, in mouse lung tissue. Responses were assessed in BALB/c mouse lung at day 7 of transient overexpression using endotracheally administered adenovirus encoding OSM (AdOSM) or empty vector (AdDel70). Whole lung extracts showed induction of IL-33 mRNA (>20-fold) and protein (10-fold increase in immunoblots) by AdOSM relative to AdDel70...
2016: Mediators of Inflammation
Renate Burger, Andreas Guenther, Katja Klausz, Matthias Staudinger, Matthias Peipp, Eva Maria Murga Penas, Stefan Rose-John, John Wijdenes, Martin Gramatzki
Interleukin (IL)-6 has an important role in the pathophysiology of multiple myeloma where it supports the growth and survival of the malignant plasma cells in the bone marrow. It belongs to a family of cytokines which use the glycoprotein (gp)130 chain for signal transduction, such as oncostatin M or leukemia inhibitory factor (LIF). Targeting IL-6 in plasma cell diseases is currently evaluated in clinical trials with monoclonal antibodies (mAbs). Here, efforts were made to elucidate the contribution of IL-6 and gp130 signaling in malignant plasma cell growth in vivo...
September 22, 2016: Haematologica
Arti Yadav, Bhavna Kumar, Theodoros N Teknos, Pawan Kumar
Recent studies have shown that IL-6 signaling plays an important role in the aggressive and metastatic phenotype of head and neck squamous cell carcinoma (HNSCC). Therefore, we hypothesized that targeting of IL-6 signaling in HNSCC could enhance the therapeutic efficacy of standard chemoradiation treatment. We used both in vitro and in vivo models to test the efficacy of Bazedoxifene (BZA), a drug that was originally developed as a newer-generation selective estrogen receptor modulator (SERM) for the treatment of postmenopausal osteoporosis...
August 22, 2016: Oncotarget
Hui Chen, Xiongze Zhang, Nanying Liao, Feng Wen
PURPOSE: Trans-signaling of interleukin (IL)-6 through its soluble receptor (sIL-6R) is critically involved in the promotion of chronic inflammatory diseases. The aim of the present study was to estimate IL-6, sIL-6R, and soluble gp130 (sgp130, a natural antagonist of IL-6 trans-signaling) concentrations in the serum and aqueous humor (AqH) of patients with diabetic retinopathy (DR). METHODS: Paired AqH and serum samples were collected from 152 consecutive diabetic patients (105 with DR and 47 without DR, NDR) and 51 healthy controls...
2016: Molecular Vision
Adam P Lightfoot, Robert G Cooper
PURPOSE OF REVIEW: This article updates on the concept that muscle-derived cytokines (myokines) play important roles in muscle health and disease. RECENT FINDINGS: Interleukin-6 (IL-6) is released from normal skeletal muscle in response to exercise, mediating both anti-inflammatory responses and metabolic adaptations, actions contradictory to the prevailing view that IL-6 is a proinflammatory cytokine that is inducing and propagating disease. The anti-inflammatory effects of IL-6 result from its trans-membrane signalling capability, via membrane-bound receptors, whereas its proinflammatory effects result instead from signalling via the soluble IL-6 receptor and gp130...
November 2016: Current Opinion in Rheumatology
Emma C Walker, Rachelle W Johnson, Yifang Hu, Holly J Brennan, Ingrid J Poulton, Jian-Guo Zhang, Brendan J Jenkins, Gordon K Smyth, Nicos A Nicola, Natalie A Sims
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are IL-6 family members with a wide range of biological functions. Human OSM (hOSM) and murine LIF (mLIF) act in mouse cells via a LIF receptor (LIFR): glycoprotein 130 (gp130) heterodimer. In contrast, murine OSM (mOSM) signals mainly via an OSM receptor (OSMR):glycoprotein 130 (gp130) heterodimer, and binds with only very low affinity to mLIFR. hOSM and mLIF stimulate bone remodelling both by reducing osteocytic sclerostin and upregulating the pro-osteoclastic factor RANKL in osteoblasts...
August 18, 2016: Journal of Biological Chemistry
J Wu, W Guo, S-Z Lin, Z-J Wang, J-T Kan, S-Y Chen, Y-Z Zhu
Doxorubicin (Dox) could trigger a large amount of apoptotic cells in the myocardium, which leads to dilated cardiomyopathy and heart failure. S-propargyl-cysteine (SPRC), a producing agent of endogenous hydrogen sulfide (H2S), possesses cardioprotective efficacy. However, the specific effect and mechanism of SPRC in Dox-induced cardiotoxicity remain elusive. Given gp130 with its main downstream signaling molecule, signal transducer and activator of transcription 3 (STAT3), is involved in cardiac myocyte survival and growth; the present study was performed to elucidate whether SPRC counteracts Dox-induced cardiotoxicity, and if so, whether the gp130/STAT3 pathway is involved in this cardioprotective activity...
2016: Cell Death & Disease
Xiaojuan Wu, Yang Cao, Hui Xiao, Chenglong Li, Jiayuh Lin
The IL-6/GP130/STAT3 pathway is crucial for tumorigenesis in multiple cancer types, including pancreatic cancer and presents as a viable target for cancer therapy. We reported Bazedoxifene, which is approved as a selective estrogen modulator by FDA, as a novel inhibitor of IL-6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL-6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL-6/GP130/STAT3 signaling in vitro and in vivo...
August 17, 2016: Molecular Cancer Therapeutics
Michael Xiang, Haesook Kim, Vincent T Ho, Sarah R Walker, Michal Bar-Natan, Melodi Anahtar, Suhu Liu, Patricia A Toniolo, Yasmin Kroll, Nichole Jones, Zachary T Giaccone, Lisa N Heppler, Darwin Q Ye, Jason J Marineau, Daniel Shaw, James E Bradner, Traci Blonquist, Donna Neuberg, Claudio Hetz, Richard M Stone, Robert J Soiffer, David A Frank
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically-available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron™), an FDA-approved anti-microbial, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells...
August 16, 2016: Blood
Juliane Lokau, Maria Agthe, Christoph Garbers
The cytokines interleukin-11 (IL-11) and IL-6 are important proteins with well-defined pro- and anti-inflammatory functions. They activate intracellular signaling cascades through a homodimer of the ubiquitously expressed signal-transducing β-receptor glycoprotein 130 (gp130). Specificity is gained through the cell- and tissue-specific expression of the nonsignaling IL-11 and IL-6 α-receptors (IL-11R and IL-6R), which determine the responsiveness of the cell to these two cytokines. IL-6 is a rare example, where its soluble receptor (sIL-6R) has agonistic properties, so that the IL-6/sIL-6R complex is able to activate cells that are usually not responsive to IL-6 alone (trans-signaling)...
2016: Mediators of Inflammation
Denise Heim, Ines Gil-Ibanez, Johannes Herden, Ann Christin Parplys, Kerstin Borgmann, Dirk Schmidt-Arras, Ansgar W Lohse, Stefan Rose-John, Henning Wege
Pro-inflammatory signaling pathways, especially interleukin 6 (IL-6), and reactive oxygen species (ROS) promote carcinogenesis in the liver. In order to elucidate the underlying oncogenic mechanism, we activated the IL-6 signal transducer glycoprotein 130 (gp130) via stable expression of a constitutively active gp130 construct (L-gp130) in untransformed telomerase-immortalized human fetal hepatocytes (FH-hTERT). As known from hepatocellular adenomas, forced gp130 activation alone was not sufficient to induce malignant transformation...
July 30, 2016: Oncotarget
Haili Xu, Timothy Radabaugh, Zhenqiang Lu, Michael Galligan, Dean Billheimer, Donata Vercelli, Anne L Wright, Terrence J Monks, Marilyn Halonen, Serrine S Lau
BACKGROUND: Proteomic approaches identifying biomarkers have been applied to asthma to only a very limited extent. METHODS: With an antibody array (RayBiotech, Norcross, GA) the relative intensity and rank differences of 444 proteins were compared in 24 plasma samples obtained at age 3, 11 from children with and 12 without asthma diagnoses at ages 5 and 9. Protein candidates identified by antibody array were quantitated by ELISA in an enlarged sample. Proteins found to differentiate children with and without asthma were also examined for association with known Year 1 asthma risk factors, eczema and wheeze...
July 19, 2016: Pediatric Allergy and Immunology
Niloufar Monhasery, Jens Moll, Carly Cuman, Manuel Franke, Larissa Lamertz, Rebecca Nitz, Boris Görg, Dieter Häussinger, Juliane Lokau, Doreen M Floss, Roland Piekorz, Eva Dimitriadis, Christoph Garbers, Jürgen Scheller
Interleukin (IL)-11 signaling is involved in various processes, including epithelial intestinal cell regeneration and embryo implantation. IL-11 signaling is initiated upon binding of IL-11 to IL-11R1 or IL-11R2, two IL-11α-receptor splice variants, and gp130. Here, we show that IL-11 signaling via IL-11R1/2:gp130 complexes occurs on both the apical and basolateral sides of polarized cells, whereas IL-6 signaling via IL-6R:gp130 complexes is restricted to the basolateral side. We show that basolaterally supplied IL-11 is transported and released to the apical extracellular space via transcytosis in an IL-11R1-dependent manner...
July 26, 2016: Cell Reports
Vibeke N Ritschel, Ingebjørg Seljeflot, Harald Arnesen, Sigrun Halvorsen, Jan Eritsland, Morten W Fagerland, Geir Ø Andersen
BACKGROUND: Reports on soluble interleukin-6 (IL-6) receptor (sIL-6R) and glycoprotein 130 (sgp130) in ST-elevation myocardial infarction (STEMI) are few and include a small number of patients. The aim of this study was to investigate the possible association between levels of these biomarkers in the acute phase of STEMI and future cardiovascular events. METHODS AND RESULTS: Circulating IL-6, sgp130, sIL-6R, and C-reactive protein (CRP) were measured in 989 STEMI patients during 2007-2011, and cardiovascular events were recorded during follow-up...
June 2016: Journal of the American Heart Association
K Tsuji, T Nakahata
A complex of soluble interleukin-6 receptor (sIL-6R) and interleukin-6 has been shown to play some roles in human hematopoiesis. It activates gp130 signal to stimulate human erythroid, megakaryocytic and primitive hematopoietic progenitor cells, which express gp130 but not IL-6R, in the presence of c-Kit signal mediated by stem cell factor (SCF). The culture system using a combination of sIL-6R, IL-6 and SCF can be useful for ex vivo expansion of human hematopoietic stem/progenitor cells and provide a novel way for gene transfer into human hematopoietic stem cells...
1997: Hematology (Amsterdam, Netherlands)
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