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Ken Tawara, Celeste Bolin, Jordan Koncinsky, Sujatha Kadaba, Hunter Covert, Caleb Sutherland, Laura Bond, Joseph Kronz, Joel R Garbow, Cheryl L Jorcyk
BACKGROUND: Systemic and chronic inflammatory conditions in patients with breast cancer have been associated with reduced patient survival and increased breast cancer aggressiveness. This paper characterizes the role of an inflammatory cytokine, oncostatin M (OSM), in the preintravasation aspects of breast cancer metastasis. METHODS: OSM expression levels in human breast cancer tissue samples were assessed using tissue microarrays, and expression patterns based on clinical stage were assessed...
June 14, 2018: Breast Cancer Research: BCR
Sunyoung Ham, Luize G Lima, Edna Pei Zhi Chai, Alexandra Muller, Richard J Lobb, Sophie Krumeich, Shu Wen Wen, Adrian P Wiegmans, Andreas Möller
Tumor-derived exosomes are being recognized as essential mediators of intercellular communication between cancer and immune cells. It is well established that bone marrow-derived macrophages (BMDMs) take up tumor-derived exosomes. However, the functional impact of these exosomes on macrophage phenotypes is controversial and not well studied. Here, we show that breast cancer-derived exosomes alter the phenotype of macrophages through the interleukin-6 (IL-6) receptor beta (glycoprotein 130, gp130)-STAT3 signaling pathway...
2018: Frontiers in Immunology
Erika Engelowski, Artur Schneider, Manuel Franke, Haifeng Xu, Ramona Clemen, Alexander Lang, Paul Baran, Christian Binsch, Birgit Knebel, Hadi Al-Hasani, Jens M Moll, Doreen M Floß, Philipp A Lang, Jürgen Scheller
Cytokine-induced signal transduction is executed by natural biological switches, which among many others control immune-related processes. Here, we show that synthetic cytokine receptors (SyCyRs) can induce cytokine signaling using non-physiological ligands. High-affinity GFP- and mCherry-nanobodies were fused to transmembrane and intracellular domains of the IL-6/IL-11 and IL-23 cytokine receptors gp130 and IL-12Rβ1/IL-23R, respectively. Homo- and heterodimeric GFP:mCherry fusion proteins as synthetic cytokine-like ligands were able to induce canonical signaling in vitro and in vivo...
May 23, 2018: Nature Communications
Larissa Lamertz, Doreen M Floss, Jürgen Scheller
Gp130 is the common receptor within the Interleukin 6 cytokine family. Gp130 consists of 6 extracellular domains followed by a small stalk region connecting the last extracellular domain with the trans-membrane domain. Whereas the first three extracellular domains bind to IL-6-type cytokines, the domains 4-6 are needed for correct positioning of the intracellular domains to facilitate Janus kinase activation after cytokine binding. Interestingly, deletion within the cytokine-binding domain resulted in cytokine-independent constitutive activation of mutant gp130 receptors...
May 19, 2018: Cytokine
Xinxin Tong, Shengjie Chen, Huanqin Zheng, Shiguang Huang, Fangli Lu
Interleukin 27 (IL-27) is a member of the IL-6/IL-12 family, and IL-27 receptor (IL-27R) consists of WSX-1 (the IL-27Rα subunit) and the signal-transducing subunit gp130. Human and mouse mast cells (MCs) express the IL-27R. To explore the expressions of IL-27/IL-27R subunits (WSX-1 and gp130) during acute ocular toxoplasmosis (OT), we established mouse model by intraocular injection of 500 Toxoplasma gondii RH strain tachyzoites. Histopathological changes were analyzed, MCs were counted by toluidine blue staining, and tryptase+ /IL-27+ MCs were examined by immunofluorescence double-staining in the eyes and cervical lymph nodes (CLNs) of T...
May 19, 2018: Parasitology Research
Sanhong Li, Jilai Tian, Hongming Zhang, Shoubing Zhou, Xiyong Wang, Lei Zhang, Jiapeng Yang, Zhigang Zhang, Zhenling Ji
Recent studies have confirmed that IL-6/GP130 targets are closely associated with tumor growth, metastasis and drug resistance. 5-Fluorouracil (5-FU) is the most common chemotherapeutic agent for colon cancer but is limited due to chemoresistance and high cytotoxicity. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator, was discovered by multiple ligand simultaneous docking and drug repositioning approaches to have a novel function as an IL-6/GP130 target inhibitor. Thus, we speculated that in colon cancer, the anti-tumor efficacy of 5-FU might be increased in combination with IL-6/GP130 inhibitors...
May 18, 2018: Apoptosis: An International Journal on Programmed Cell Death
Kristian Holz, Marco Prinz, Stefanie M Brendecke, Alexandra Hölscher, Fengyuan Deng, Hans-Willi Mitrücker, Stefan Rose-John, Christoph Hölscher
gp130 cytokines are differentially involved in regulating the T helper (H) 17-driven pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of human multiple sclerosis. Interleukin (IL)-6 directly promotes the development of TH17 cells through the gp130/IL-6R complex. By contrast, IL-27 has been shown to suppress a TH17 immune response by gp130/IL-27R-alpha (α) receptor ligation. The IL-27-dependent regulation of a TH17 development could be mediated on the level of CD4 T cells. However, because IL-27 also suppresses the secretion of the TH17-driving cytokines IL-6 and IL-12/23p40 in accessory cells, TH17 immune responses may also be controlled by IL-27 on the level of macrophages and/or neutrophils...
2018: Frontiers in Immunology
Shuang Liu, Li-Xin Liu, Yun-Long Zhang, Song Lai, Yun-Peng Xie, Nan-Nan Li, Hong-Xia Wang, Yun-Long Xia, Ying Liu, Hui-Hua Li
BACKGROUND/AIMS: Cardiac remodeling is a critical pathogenetic process leading to heart failure. Suppressor of cytokine signaling-3 (SOCS3) is demonstrated as a key negative regulator of the gp130 receptor to inhibit cardiac hypertrophy. However, the role of SOCS3 in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. METHODS: Cardiac-specific SOCS3 knockout (SOCS3cKO) and wild-type (WT) C57BL/6J mice were subjected to uninephrectomy and DOCA-salt for 3 weeks...
May 10, 2018: Cellular Physiology and Biochemistry
Ping Miao, Xiao Wei Zhou, Ping Wang, Rong Zhao, Ninan Chen, Chao Ying Hu, Xue Hua Chen, Liu Qian, Qi Wen Yu, Ji Ying Zhang, Rong Xu, Dong Yi He, Lian Bo Xiao, Pu Li, Mason Lu, Dong Qing Zhang
We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody-induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor α (IL-6Rα), gp130, receptor activator of nuclear factor κB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Rα; WNT5A and RANKL levels were detected...
April 17, 2018: Oncotarget
Sara La Manna, Eunmi Lee, Maria Ouzounova, Concetta Di Natale, Ettore Novellino, Antonello Merlino, Hasan Korkaya, Daniela Marasco
Suppressor of cytokine signaling (SOCS) family of proteins plays critical role in the regulation of immune responses controlling JAK/STAT mediated inflammatory cytokines. Among the members, SOCS1 and SOCS3 contain a kinase inhibitory region (KIR) and SOCS3 binds to JAK/STAT/gp130 complex by inhibiting the downstream signaling and suppressing inflammatory cytokines. Loss or reduced levels of SOCS3 have been linked to cancer-associated inflammation and suppressive immunity leading to enhanced tumour growth and metastasis...
May 11, 2018: International Journal of Cancer. Journal International du Cancer
Xiang Chen, Jilai Tian, Gloria H Su, Jiayuh Lin
BACKGROUND: Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunctions of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance. OBJECTIVE: We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer...
April 30, 2018: Current Cancer Drug Targets
Jun Ma, Xiao Song, Xiaowu Xu, Yiping Mou
Purpose: Our aim was to detect the potential role of IL-11 in the development of chemo-resistance in gastric cancer and to reveal the mechanism involved in the process. Materials and Methods: Here, we used flow cytometry to examine the percentage of CAFs in tumor samples from chemo-resistant and -sensitive gastric cancer patients. Using MTT assay, we detected the cell viability under different conditions. Using qRT-PCR and Western blotting, we determined the target expressions in mRNA and protein levels...
April 20, 2018: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Masanobu Kimura, Hiroyuki Nagashima, Yuko Okuyama, Naoto Ishii, Takanori So
TRAF2 and TRAF5 constitutively bind to gp130 and inhibit IL-6-driven activation of STAT3 in CD4+ T cells, which limits the differentiation of pro-inflammatory IL-17-producing helper T cells that require IL-6-receptor signals for their development. However, it is not known how the interaction between TRAF and gp130 negatively regulates STAT3 activity in the IL-6-receptor complex. We hypothesized that TRAF proteins associated with gp130 would limit activation processes of JAK kinases, which are crucial for STAT3 activation...
April 13, 2018: International Immunology
Yuichi Tamura, Carole Phan, Ly Tu, Morane Le Hiress, Raphaël Thuillet, Etienne-Marie Jutant, Elie Fadel, Laurent Savale, Alice Huertas, Marc Humbert, Christophe Guignabert
Pulmonary arterial hypertension (PAH) is characterized by a progressive accumulation of pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterioles leading to the narrowing of the lumen, right heart failure, and death. Although most studies have supported the notion of a role for IL-6/glycoprotein 130 (gp130) signaling in PAH, it remains unclear how this signaling pathway determines the progression of the disease. Here, we identify ectopic upregulation of membrane-bound IL-6 receptor (IL6R) on PA-SMCs in PAH patients and in rodent models of pulmonary hypertension (PH) and demonstrate its key role for PA-SMC accumulation in vitro and in vivo...
May 1, 2018: Journal of Clinical Investigation
Andrew N Wilkinson, Kate H Gartlan, Greg Kelly, Luke D Samson, Stuart D Olver, Judy Avery, Nienke Zomerdijk, Siok-Keen Tey, Jason S Lee, Slavica Vuckovic, Geoffrey R Hill
IL-6 mediates broad physiological and pathological effects through its receptor signal transducing unit gp130. Due to the reportedly wide cellular expression of gp130, IL-6 is thought to signal ubiquitously via gp130 complex formation with membrane-bound IL-6Rα or soluble IL-6Rα. gp130 signaling primarily induces p-STAT3 and p-STAT1. In contrast to the previous dogma, we show in this article that circulating mouse and human granulocytes are unable to induce p-STAT3 or p-STAT1 after stimulation with IL-6 or an IL-6/soluble IL-6R complex...
May 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Bo Ma, Lan Yang, Ruihua Jing, Jie Liu, Yumeng Quan, Qiaoyan Hui, Jingming Li, Li Qin, Cheng Pei
The purpose of this work was to determine the effects of interleukin-6 (IL-6) on the development of posterior capsular opacification (PCO) in vitro and in vivo. Western blot and real-time PCR were used to test the IL-6-induced epithelial-mesenchymal transition (EMT) marker α-smooth muscle actin (α-SMA), the extracellular matrix (ECM) markers fibronectin (Fn) and type I collagen (COL-1), transforming growth factor β2 (TGF-β2 ), and the activation and role of the JAK/STAT3 signaling pathway in human lens epithelial cells (HLECs)...
April 1, 2018: Experimental Eye Research
Alexandra A Korotaeva, Elena V Samoilova, Daria A Chepurnova, Irina V Zhitareva, Yulia A Shuvalova, Nina V Prokazova
PURPOSE: Recent studies indicate that the effects of interleukin 6 (IL-6) realized via soluble IL-6 receptor (sIL-6R) facilitate the development of various pathological processes. Soluble gp130 (sgp130) is a naturally occurring inhibitor of signal transduction via this pathway. In this study, we assessed the relationship between circulating levels of IL-6, sIL-6R and sgp130 and severity of coronary atherosclerosis in patients with stable coronary artery disease (CAD). METHODS: Plasma levels of IL-6, sIL-6R and sgp130 were measured in patients with atherosclerotic coronary lesions (n = 128, group 1) and with intact coronary arteries (n = 48, group 2)...
April 26, 2018: Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals
Paul Baran, Selina Hansen, Georg H Waetzig, Mohammad Akbarzadeh, Larissa Lamertz, Heinrich J Huber, M Reza Ahmadian, Jens M Moll, Jürgen Scheller
Interleukin (IL-)6 is the major pro-inflammatory cytokine within the IL-6 family. IL-6 signals via glycoprotein 130 (gp130) and the membrane-bound or soluble IL-6 receptor (IL-6R), referred to as classic or trans-signaling, respectively. Whereas inflammation triggers IL-6 expression, eventually rising to nanogram/ml serum levels, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) are constitutively present in the upper nanogram/ml range. Calculations based on intermolecular affinities have suggested that systemic IL-6 is immediately trapped in IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes, indicating that sIL-6R and sgp130 constitute a buffer system that increases the serum half-life of IL-6 or restricts systemic IL-6 signaling...
May 4, 2018: Journal of Biological Chemistry
Maria Agthe, Yvonne Garbers, Joachim Grötzinger, Christoph Garbers
BACKGROUND/AIMS: The cytokine interleukin-11 (IL-11) has important pro- and anti-inflammatory functions. It activates its target cells through binding to the IL-11 receptor (IL-11R), and the IL-11/IL-11R complex recruits a homodimer of glycoprotein 130 (gp130). N-linked glycosylation, a post-translational modification where complex oligosaccharides are attached to the side chain of asparagine residues, is often important for stability, folding and biological function of cytokine receptors...
2018: Cellular Physiology and Biochemistry
Fumihiro Sanada, Yoshiaki Taniyama, Jun Muratsu, Rei Otsu, Hideo Shimizu, Hiromi Rakugi, Ryuichi Morishita
Cellular senescence is the complex process of deterioration that drives the aging of an organism, resulting in the progressive loss of organ function and eventually phenotypic aging. Senescent cells undergo irreversible growth arrest, usually by inducing telomere shortening. Alternatively, senescence may also occur prematurely in response to various stress stimuli, such as oxidative stress, DNA damage, or activated oncogenes. Recently, it has been shown that IGF binding protein-5 (IGFBP-5) with the induction of the tumor suppressor p53 is upregulated during cellular senescence...
2018: Frontiers in Endocrinology
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