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https://www.readbyqxmd.com/read/27893707/blockade-of-the-il-6-trans-signalling-stat3-axis-suppresses-cachexia-in-kras-induced-lung-adenocarcinoma
#1
A Miller, L McLeod, S Alhayyani, A Szczepny, D N Watkins, W Chen, P Enriori, W Ferlin, S Ruwanpura, B J Jenkins
Lung cancer is the leading cause of cancer death worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia; however, the mechanisms by which IL-6 promotes muscle wasting in lung cancer cachexia are ill-defined. In this study, we report that the gp130(F/F) knock-in mouse model displaying hyperactivation of the latent transcription factor STAT3 via the common IL-6 cytokine family signalling receptor, gp130, develops cachexia during Kras-driven lung carcinogenesis...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27886185/hyper-il-6-a-potent-and-efficacious-stimulator-of-rgc-regeneration
#2
D Fischer
Mature retinal ganglion cells (RGCs) normally fail to regenerate injured axons and die soon after optic nerve injury. Research over the last two decades has demonstrated that application of IL-6-like cytokines or activation of respective downstream signaling pathways promote neuroprotection and optic nerve regeneration. However, the overall beneficial effects of natural cytokines remain usually rather moderate, possibly due to intrinsic signaling pathway inhibitors, such as PTEN or SOCS3, or a limited expression of specific cytokine receptors in RGCs...
November 25, 2016: Eye
https://www.readbyqxmd.com/read/27879265/il-6-signaling-in-peripheral-blood-t-cells-predicts-clinical-outcome-in-breast-cancer
#3
Lei Wang, Andrea K Miyahira, Diana Simons, Xuyang Lu, Andrew Chang, Carrie Wang, Maria Suni, Vernon C Maino, Frederick M Dirbas, John H Yim, James Waisman, Peter P Lee
Interleukin-6 (IL-6) is a pleiotropic cytokine with both pro- and anti-inflammatory properties which acts directly on cancer cells to promote their survival and proliferation. Elevated serum IL-6 levels negatively correlate with survival of cancer patients, which is generally attributed to the direct effects of IL-6 on cancer cells. How IL-6 modulates the host immune response in cancer patients is unclear. Here we show the IL-6 signaling response in peripheral blood T cells is impaired in breast cancer (BC) patients and is associated with blunted Th17 differentiation...
November 22, 2016: Cancer Research
https://www.readbyqxmd.com/read/27863335/il-6-trans-signaling-is-another-pathway-to-upregulate-osteopontin
#4
Takaaki Uchibori, Kazuyuki Matsuda, Takahiro Shimodaira, Mitsutoshi Sugano, Takeshi Uehara, Takayuki Honda
BACKGROUND: Osteopontin (OPN) is a pro-fibrotic molecule upregulated by pro-inflammatory cytokines. Interleukin (IL)-6 functions downstream of IL-1β and has unique signal pathways: classic- or trans-signaling via membrane-bound IL-6R or soluble IL-6R (sIL-6R). We investigated the effect of IL-6 trans-signaling on the upregulation of OPN. METHODS: We used THP-1 cells and THP-1 macrophages differentiated from THP-1 cells using phorbol 12-myristate 13-acetate (PMA)...
November 15, 2016: Cytokine
https://www.readbyqxmd.com/read/27825285/leukemia-inhibitory-factor-contributed-to-reactive-astrogliosis-via-activation-of-stat3-signaling-after-intracerebral-hemorrhage-in-rats
#5
Hua-Jun Zhou, Xi Yang, Han-Jin Cui, Tao Tang, Jian-Hua Zhong, Jie-Kun Luo, A-Li Yang, Qi-Mei Zhang, Jing-Hua Zhou, Qiang Zhang
Reactive astrogliosis has been occurred after intracerebral hemorrhage (ICH). Leukemia inhibitory factor (LIF) can act as a modulator for glial gene expression. Signal transducer and activator of transcription3 (STAT3) is a critical regulator of reactive astrogliosis. The present study tested whether endogenous leukemia inhibitory factor (LIF) acted on intracerebral hemorrhage (ICH)-induced reactive astrogliosis via STAT3 signaling pathway. Rats were divided into three parts of experiments: (1) Rats received either an ICH or a needle insertion (sham)...
November 8, 2016: Journal of Neurotrauma
https://www.readbyqxmd.com/read/27798371/oncostatin-m-preconditioned-mesenchymal-stem-cells-alleviate-bleomycin-induced-pulmonary-fibrosis-through-paracrine-effects-of-the-hepatocyte-growth-factor
#6
Ying-Wei Lan, Si-Min Theng, Tsung-Teng Huang, Kong-Bung Choo, Chuan-Mu Chen, Han-Pin Kuo, Kowit-Yu Chong
: : Mesenchymal stem cells (MSCs) are widely considered for treatment of pulmonary fibrosis based on the anti-inflammatory, antifibrotic, antiapoptotic, and regenerative properties of the cells. Recently, elevated levels of oncostatin M (OSM) have been reported in the bronchoalveolar lavage fluid of a pulmonary fibrosis animal model and in patients. In this work, we aimed to prolong engrafted MSC survival and to enhance the effectiveness of pulmonary fibrosis transplantation therapy by using OSM-preconditioned MSCs...
October 18, 2016: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/27759082/jak-stat-signaling-regulates-the-proliferation-and-neurogenic-potential-of-m%C3%A3-ller-glia-derived-progenitor-cells-in-the-avian-retina
#7
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
https://www.readbyqxmd.com/read/27747134/interleukin-6-a-constitutive-modulator-of-glycoprotein-130-neuroinflammatory-and-cell-survival-signaling-in-retina
#8
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
https://www.readbyqxmd.com/read/27740621/tetraspanin-cd9-stabilizes-gp130-by-preventing-its-ubiquitin-dependent-lysosomal-degradation-to-promote-stat3-activation-in-glioma-stem-cells
#9
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
https://www.readbyqxmd.com/read/27737952/initiation-of-antiretroviral-therapy-in-early-hiv-infection-reduces-but-does-not-abrogate-chronic-residual-inflammation
#10
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
https://www.readbyqxmd.com/read/27708132/instructive-role-of-the-microenvironment-in-preventing-renal-fibrosis
#11
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
https://www.readbyqxmd.com/read/27703303/regulation-of-il-33-by-oncostatin-m-in-mouse-lung-epithelial-cells
#12
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
https://www.readbyqxmd.com/read/27658435/due-to-interleukin-6-type-cytokine-redundancy-only-glycoprotein-130-receptor-blockade-efficiently-inhibits-myeloma-growth
#13
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
https://www.readbyqxmd.com/read/27564254/bazedoxifene-enhances-the-anti-tumor-effects-of-cisplatin-and-radiation-treatment-by-blocking-il-6-signaling-in-head-and-neck-cancer
#14
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
https://www.readbyqxmd.com/read/27563232/increased-levels-of-il-6-sil-6r-and-sgp130-in-the-aqueous-humor-and-serum-of-patients-with-diabetic-retinopathy
#15
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
https://www.readbyqxmd.com/read/27548653/the-role-of-myokines-in-muscle-health-and-disease
#16
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
https://www.readbyqxmd.com/read/27539849/murine-oncostatin-m-acts-via-leukemia-inhibitory-factor-receptor-to-phosphorylate-stat3-but-not-stat1-an-effect-that-protects-bone-mass
#17
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
https://www.readbyqxmd.com/read/27537522/gp130-mediated-stat3-activation-by-s-propargyl-cysteine-an-endogenous-hydrogen-sulfide-initiator-prevents-doxorubicin-induced-cardiotoxicity
#18
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...
August 18, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27535971/bazedoxifene-as-a-novel-gp130-inhibitor-for-pancreatic-cancer-therapy
#19
Xiaojuan Wu, Yang Cao, Hui Xiao, Chenglong Li, Jiayuh Lin
The IL6/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 IL6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL6/GP130/STAT3 signaling in vitro and in vivo In addition, IL6, but not INFγ, rescued Bazedoxifene-mediated reduction of cell viability...
November 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27531676/gene-expression-based-discovery-of-atovaquone-as-a-stat3-inhibitor-and-anti-cancer-agent
#20
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
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