DOCSLIB.ORG

(CS-ⅣA-Be), a Novel IL-6R Antagonist, Inhibits IL-6/STAT3

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(CS-ⅣA-Be), a Novel IL-6R Antagonist, Inhibits IL-6/STAT3 Author Manuscript Published OnlineFirst on February 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0551 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Chikusetsusaponin Ⅳa butyl ester (CS-Ⅳa-Be), a novel IL-6R antagonist, inhibits IL-6/STAT3 signaling pathway and induces cancer cell apoptosis Jie Yang 1, 2, Shihui Qian 2, Xueting Cai 1, 2, Wuguang Lu 1, 2, Chunping Hu 1, 2, * Xiaoyan Sun1, 2, Yang Yang1, 2, Qiang Yu 3, S. Paul Gao 4, Peng Cao 1, 2 1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China 2. Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China 3. Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China 4. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY10065, USA Running title: CS-Ⅳa-Be, a novel IL-6R antagonist, inhibits IL-6/STAT3 Keywords: Chikusetsusaponin Ⅳ a butyl ester (CS- Ⅳ a-Be), STAT3, IL-6R, antagonist, cancer Grant support: P. Cao received Jiangsu Province Funds for Distinguished Young Scientists (BK20140049) grant, J. Yang received National Natural Science Foundation of China (No. 81403151) grant, and X.Y. Sun received National Natural Science Foundation of China (No. 81202576) grant. Corresponding author: Peng Cao Institute: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China Mailing address: 100#, Shizi Street, Hongshan Road, Nanjing, Jiangsu, China Tel: +86-25-85608666 Fax: +86-25-85608666 Email address: [email protected] The first co-authors: Jie Yang and Shihui Qian The authors disclose no potential conflicts of interest. 1 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0551 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abbreviations IL-6: Interleukin 6; STAT: Signal transducer and activator of transcription; GP130: Glycoprotein 130; IL-6Rα: Interleukin 6 receptor alpha; LIFR: Leukemia inhibitory factor receptor; LeptinR: Leptin receptor; TRAIL: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand; DR: Death receptor; LIF: Leukemia inhibitory factor; OSM: Oncostatin M; JAK: Janus kinase; c-FLIP: cellular FLICE-like inhibitory protein; Bcl-xL: B-cell lymphoma-extra large; Mcl-1: Myeloid cell leukemia 1; IAP: Inhibitor of apoptosis protein; MTT: Methyl thiazolyl tetrazolium; TNF-α: Tumor necrosis factor alpha; EGF: Epidermal growth factor; IFN-γ: Interferon gamma; SDS-PAGE: Sodium dodecyl sulfate polyacrylamide gel electrophoresis; PVDF: polyvinylidene fluoride; GM-CSF: Granulocyte-macrophage colony-stimulating factor; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; ROS: Reactive oxygen species; TYK2: Tyrosine kinase 2; EGFR: Epidermal growth factor receptor; IGF1R: Insulin-like growth factor 1 receptor; PDGFRα: Platelet-derived growth factor receptor α; FGFR: Fibroblast growth factor receptor; ELISA: Enzyme linked immunosorbent assay; EMSA: Electrophoretic mobility shift assay; MST: Microscale thermophoresis; JNK: c-Jun N-terminal kinase; ERK: Extracellular signal-regulated kinases; PARP: Poly ADP ribose polymerase; MAPK: Mitogen-activated protein kinase; TNF-α: Tumor necrosis factor alpha; PTPase: Protein tyrosine phosphatase; XIAP: X-linked inhibitor of apoptosis. 2 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0551 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract The activation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling is associated with the pathogenesis of many cancers. Agents that suppress IL-6/STAT3 signaling have cancer therapeutic potential. In this study, we found that chikusetsusaponin Ⅳa butyl ester (CS-Ⅳa-Be), a triterpenoid saponin extracted from Acanthopanas gracilistylus W.W.Smith, induced cancer cell apoptosis. CS-Ⅳa-Be inhibited constitutive and IL-6-induced STAT3 activation, repressed STAT3 DNA binding activity, STAT3 nuclear translocation, IL-6-induced STAT3 luciferase reporter activity, IL-6-induced STAT3 regulated anti-apoptosis genes expression in MDA-MB-231 cells and IL-6-induced TF-1 cell proliferation. Surprisingly, CS-Ⅳa-Be inhibited IL-6 family cytokines rather than other growth factors induced STAT3 activation. Further studies indicated that CS-Ⅳa-Be is an antagonist of IL-6 receptor via directly binding to the IL-6Rα with a Kd of 663±74 nM and the GP130 (IL-6Rβ) with a Kd of 1660±243 nM, interfering the binding of IL-6 to IL-6R (IL-6Rα and GP130) in vitro and in cancer cells. The inhibitory effect of CS-Ⅳa-Be on the IL-6-IL-6Rα-GP130 interaction was relatively specific as CS-Ⅳa-Be showed higher affinity to IL-6Rα than to LIFR (Kd: 4990±915 nM) and LeptinR (Kd: 4910±1240 nM). We next demonstrated that CS-Ⅳa-Be not only directly induced cancer cell apoptosis but also sensitized MDA-MB-231 cells to TRAIL-induced apoptosis via up-regulating DR5. Our findings suggest that CS-Ⅳa-Be as a novel IL-6R antagonist inhibits IL-6/STAT3 signaling pathway and sensitizes the MDA-MB-231 cells to TRAIL induced cell death. 3 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0551 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Interleukin 6 (IL-6) is a pleiotropic cytokine mediating cancer associated chronic inflammation and inflammatory response, plays important roles in the tumorigenesis (1). IL-6 possesses three topologically distinct receptor binding sites: site 1 for binding to the 80 kDa chain IL-6Rα, and sites 2 and 3 for interacting with the two subunits of the signaling chain glycoprotein 130 (GP130). The IL-6 signaling transduces after the homodimerization of GP130, which becomes associated with IL-6-binding chain (IL-6Rα) in the presence of IL-6. (2). As a common receptor, GP130 also transduces signals delivered by the leukemia inhibitory factor (LIF), the IL-11, the oncostatin M (OSM) and the others (3). Signal transducer and activator of transcription 3 (STAT3), the key factor mediating the IL-6-induced signaling becomes tyrosine phosphorylated by IL-6 induced cytokine receptor-associated kinases, the Janus kinase (JAK) family proteins (4). The IL-6/STAT3 signaling pathway mediates tumor immune suppression (5), tumor cell survival, pre-metastatic niche formation and chemotherapy resistance (6). Breast cancer is the most common malignancy and the primary cause of cancer-related death in women worldwide (7). IL-6/JAK/STAT3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the breast tumor microenvironment that promotes cancer cell growth, invasion and metastasis (8) (9). Increasing clinical data have indicated that the circulating levels of 4 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0551 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. IL-6 in breast cancer patients correlate with clinical tumor stage and poor prognosis. IL-6 plays two distinct roles in breast cancer: the systemic IL-6, reflecting whole body metabolic and inflammatory status, is correlated with poor prognosis, advanced disease and metastasis; the paracrine and autocrine IL-6 signaling controls cancer cell growth, cancer stem cell renewal and metastasis (10) (11). In summary, the IL-6 mediated excessive STAT3 activation plays important roles in breast cancer. Inhibitors of the IL-6/STAT3 signaling pathway should be effective against the cancers with high levels of STAT3 activation. As a matter of fact, JAK3 inhibitor tofacitinib (12, 13) and IL-6Rα monoclonal antibody tocilizumab (14) have been used in clinical trial. However, no natural IL-6/STAT3 inhibitory compound has been used in cancer clinical trial. Identifying novel compounds that suppress the JAKs signaling or antagonize IL-6R is a pressing issue to prevent and treat the cancers with aberrant activated IL-6/STAT3 signaling. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising target for cancer therapy because it preferentially induces cancer cell apoptosis with little or no effects on normal cells (15). However, some highly malignant cancers, including breast cancer, (16) are resistant to TRAIL induced apoptosis. The resistance of cancer cells to TRAIL occur at various points of the TRAIL signaling pathways, dysfunctions of the death receptors DR4 and DR5, over expression of cellular FLICE-like inhibitory protein (c-FLIP), B-cell lymphoma-extra 5 Downloaded from mct.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0551 Author manuscripts have been
Load more

Recommended publications
  • BCMA-Targeted Immunotherapy for Multiple Myeloma Bo Yu1, Tianbo Jiang2 and Delong Liu2*
    Yu et al. Journal of Hematology & Oncology (2020) 13:125 https://doi.org/10.1186/s13045-020-00962-7 REVIEW Open Access BCMA-targeted immunotherapy for multiple myeloma Bo Yu1, Tianbo Jiang2 and Delong Liu2* Abstract B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development. Keywords: B cell maturation antigen, BCMA, Belantamab mafodotin, CAR-T, Antibody-drug conjugate, Bispecific T cell engager Introduction B cell maturation antigen (BCMA) Recent advances in novel therapeutics such as prote- BCMA is encoded by a 2.92-kb TNFRSF17 gene located asome inhibitors (PI) and immunomodulatory drugs on the short arm of chromosome 16 (16p13.13) and (IMiD) have significantly improved the treatment out- composed of 3 exons separated by 2 introns (Fig. 1). comes in patients with multiple myeloma (MM) [1–8]. BCMA is a 184 amino acid and 20.2-kDa type III trans- However, most MM patients eventually relapse due to membrane glycoprotein, with the extracellular N the development of drug resistance [9]. In addition, terminus containing a conserved motif of 6 cysteines many of the current popular target antigens, such as [18–21].
    [Show full text]
  • Kcnorman 1.Pdf
    A Computational Systems Approach to Elucidate New Mechanisms Involved in Progressive Lung Disease by Katy Norman A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biomedical Engineering) in the University of Michigan 2020 Doctoral Committee: Assistant Professor Kelly Arnold, Chair Professor Jeffrey Curtis Professor Jennifer Linderman Professor Bethany Moore Professor David Sept Katy C. Norman [email protected] ORCID iD: 0000-0001-8841-0212 © Katy C. Norman 2020 Acknowledgements When I look back on myself in 2015 as I just entered the PhD program, I have to give a little laugh about all the surprises and changes that have happened along the way. I have grown more than I could ever have imagined – I have become so much more comfortable and confident in my communication skills, in my scientific skills, and in myself. These changes and this growth could not have happened without my huge support network, and I am honored to have the chance to thank everyone for what they have given me and for what they have helped me achieve. I would first like to thank my adviser, Kelly Arnold, for giving me a chance to try out computational systems biology research when I had absolutely no background in the field coming in. I appreciate how you were easily able to create a space where I felt comfortable to learn, to ask questions, and to make mistakes as I worked towards gaining expertise in this field. Thank you for always being there for me with extra support when my nerves were getting the best of me before big presentations or before a big deadline, and for supporting my involvement in activities outside of the lab as well.
    [Show full text]
  • GP130 Cytokines in Breast Cancer and Bone
    cancers Review GP130 Cytokines in Breast Cancer and Bone Tolu Omokehinde 1,2 and Rachelle W. Johnson 1,2,3,* 1 Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; [email protected] 2 Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA 3 Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA * Correspondence: [email protected]; Tel.: +1-615-875-8965 Received: 14 December 2019; Accepted: 29 January 2020; Published: 31 January 2020 Abstract: Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment.
    [Show full text]
  • Due to Interleukin-6 Type Cytokine Redundancy Only Glycoprotein 130 Receptor Blockade Efficiently Inhibits Myeloma Growth
    Plasma Cell Disorders SUPPLEMENTARY APPENDIX Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth Renate Burger, 1 Andreas Günther, 1 Katja Klausz, 1 Matthias Staudinger, 1 Matthias Peipp, 1 Eva Maria Murga Penas, 2 Stefan Rose-John, 3 John Wijdenes 4 and Martin Gramatzki 1 1Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany; 2Institute of Human Genetics, Christian-Albrechts-University Kiel and Uni - versity Medical Center Schleswig-Holstein, Kiel, Germany; 3Department of Biochemistry, Christian-Albrechts-University of Kiel, Medical Faculty, Germany and 4Gen-Probe/Diaclone SAS, Besançon, France ©2017 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2016.145060 Received: February 25, 2016. Accepted: September 14, 2016. Pre-published: September 22, 2016. Correspondence: [email protected] SUPPLEMENTARY METHODS Cell lines and culture Cell lines INA-6, INA-6.Tu1 and B9 were cultivated in RPMI-1640 with GlutaMax™-I, 25 mM HEPES (Gibco®/Life Technologies GmbH, Darmstadt, Germany), 10% (v/v) heat-inactivated fetal bovine serum (FBS) (HyClone; Perbio Science, Erembodegen, Belgium), and antibiotics (R10+ medium) supplemented with 2.5 ng/ml recombinant huIL-6 (Gibco®/Life Technologies GmbH, Darmstadt, Germany). The cell lines are routinely confirmed to be negative for mycoplasma contamination (Venor™GeM Mycoplasma Detection Kit, Sigma-Aldrich, St. Louis, MO). Cytokines and other reagents Recombinant huIL-6 was purchased from Gibco®/Life Technologies (Darmstadt, Germany), huLIF was from Reliatech (Wolfenbüttel, Germany). Recombinant muIL-6 was obtained from Peprotech (Rocky Hill, NJ), and soluble muIL-6R was from R&D Systems (Minneapolis, MN).
    [Show full text]
  • Evolutionary Divergence and Functions of the Human Interleukin (IL) Gene Family Chad Brocker,1 David Thompson,2 Akiko Matsumoto,1 Daniel W
    UPDATE ON GENE COMPLETIONS AND ANNOTATIONS Evolutionary divergence and functions of the human interleukin (IL) gene family Chad Brocker,1 David Thompson,2 Akiko Matsumoto,1 Daniel W. Nebert3* and Vasilis Vasiliou1 1Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO 80045, USA 2Department of Clinical Pharmacy, University of Colorado Denver, Aurora, CO 80045, USA 3Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267–0056, USA *Correspondence to: Tel: þ1 513 821 4664; Fax: þ1 513 558 0925; E-mail: [email protected]; [email protected] Date received (in revised form): 22nd September 2010 Abstract Cytokines play a very important role in nearly all aspects of inflammation and immunity. The term ‘interleukin’ (IL) has been used to describe a group of cytokines with complex immunomodulatory functions — including cell proliferation, maturation, migration and adhesion. These cytokines also play an important role in immune cell differentiation and activation. Determining the exact function of a particular cytokine is complicated by the influence of the producing cell type, the responding cell type and the phase of the immune response. ILs can also have pro- and anti-inflammatory effects, further complicating their characterisation. These molecules are under constant pressure to evolve due to continual competition between the host’s immune system and infecting organisms; as such, ILs have undergone significant evolution. This has resulted in little amino acid conservation between orthologous proteins, which further complicates the gene family organisation. Within the literature there are a number of overlapping nomenclature and classification systems derived from biological function, receptor-binding properties and originating cell type.
    [Show full text]
  • Open Chen-Thesis Finalv5.Pdf
    The Pennsylvania State University The Graduate School Department of Neural and Behavioral Sciences EPIGENETIC ANALYSIS OF IMMUNE ASSOCIATED SIGNALING MOLECULES DURING MOUSE RETINA DEVELOPMENT A Thesis in Anatomy by Chen Yang © 2013 Chen Yang Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science May 2013 The thesis of Chen Yang was reviewed and approved* by the following: Samuel Shao-Min Zhang Assistant Professor of Neural and Behavioral Sciences Thesis Advisor Colin J. Barnstable Department Head of Neural and Behavioral Sciences Professor of Neural and Behavioral Sciences Patricia J. McLaughlin Professor of Neural and Behavioral Sciences Director of Graduate Program in Anatomy *Signatures are on file in the Graduate School. ii ABSTRACT The retina is an immune-privileged organ. Many autoimmune diseases, such as AMD, glaucoma, and diabetic retinopathy, are caused by excessive inflammatory responses targeting self-tissue. The physiological functions of extracellular and intracellular signaling molecules of immune responses have been well characterized. The epigenetic aspects of these molecules in the retina, however, have not been well elucidated. In this study, we examined the expression of selected immune-related genes, and their transcriptional accessibility via epigenetic mapping, cluster analysis, and RT-PCR. Among these genes, interleukin receptor related genes and intracellular signaling molecules exhibit higher transcriptional accessibility. Epigenetic mapping of the toll-like receptor (TLR) family revealed that 3 out of 13 TLRs exhibit H3K4me2 accumulation during retina development, suggesting that TLR2, TLR3, and TLR9 are the only TLR members expressed in the retina. Most of the NF-κB signaling molecules exhibited transcriptional accessibility, implying their essential roles in inflammatory regulation during retina maturation.
    [Show full text]
  • Glycosylation of Immune Receptors in Cancer
    cells Review Glycosylation of Immune Receptors in Cancer Ruoxuan Sun, Alyssa Min Jung Kim and Seung-Oe Lim * Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute of Drug Discovery, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; [email protected] (R.S.); [email protected] (A.M.J.K.) * Correspondence: [email protected]; Tel.: +1-765-494-3531 Abstract: Evading host immune surveillance is one of the hallmarks of cancer. Immune checkpoint therapy, which aims to eliminate cancer progression by reprogramming the antitumor immune response, currently occupies a solid position in the rapidly expanding arsenal of cancer therapy. As most immune checkpoints are membrane glycoproteins, mounting attention is drawn to asking how protein glycosylation affects immune function. The answers to this fundamental question will stimulate the rational development of future cancer diagnostics and therapeutic strategies. Keywords: glycosylation; N-glycan; immune receptor; immune checkpoint therapy; cancer 1. Introduction The immune system can eliminate malignancy at an early stage by recognizing the antigenic peptide epitope presented by neoplastically transformed cells [1,2]. However, a subset of tumor cells may evolve to coexist with antitumor immunity by a process defined as immunoediting [3]. To combat the immune attack and maintain the balance with the host, cancer cells develop a series of approaches such as (1) downregulation of antigen Citation: Sun, R.; Kim, A.M.J.; Lim, presentation to make them invisible to immunity/the immune system, (2) production S.-O. Glycosylation of Immune of immunomodulatory cytokines to establish an immune suppressive environment, and Receptors in Cancer. Cells 2021, 10, (3) expression of surface immune checkpoint proteins such as programmed cell death 1 1100.
    [Show full text]
  • Snapshot: Cytokines III Cristina M
    SnapShot: Cytokines III Cristina M. Tato and Daniel J. Cua Schering-Plough Biopharma (Formerly DNAX Research), Palo Alto, CA 94304, USA Cytokine Receptor Source Targets Major Function Disease Association TNFα Murine: Macrophages, Neutrophils, Inflammatory; ↓ = disregulated fever; increased TNFR,p55; TNFR,p75 monocytes, T cells, macrophages, promotes activation susceptibility to bacterial infection; others monocytes, and production of enhanced resistance to LPS-induced septic Human: endothelial cells acute-phase proteins shock TNFR,p60; TNFR,p80 ↑ = exacerbation of arthritis and colitis LTα Murine: T cells, B cells Many cell types Promotes activation ↓ = defective response to bacterial TNFR,p55; TNFR,p75 and cytotoxicity; pathogens; absence of peripheral lymph development of lymph nodes and Peyer’s patches Human: nodes and Peyer’s TNFR,p60; TNFR,p80 patches LTβ LTβR T cells, B cells Myeloid cells, other Peripheral lymph ↓ = increased susceptibility to bacterial cell types node development; infection; absence of lymph nodes and proinflammatory Peyer’s patches ↑ = ectopic lymph node formation LIGHTa LTβR, DcR3, HVEM Activated T cells, B cells, NK cells, Costimulatory; ↓ = defective CD8 T cell costimulation monocytes, DCs DCs, other tissue promotes CTL activity TWEAK Fn14 Monocytes, Tissue progenitors, Proinflammatory; macrophages, epithelial, promotes cell growth endothelial endothelial for tissue repair and remodeling APRIL TACI, BAFF-R, BCMA Macrophages, DCs B cell subsets Promotes T cell- ↓ = impaired class switching to IgA independent
    [Show full text]
  • Structure and Mechanism of Receptor Sharing by the IL-10R2 Common Chain
    Structure Article Structure and Mechanism of Receptor Sharing by the IL-10R2 Common Chain Sung-il Yoon,1,4 Brandi C. Jones,1 Naomi J. Logsdon,1 Bethany D. Harris,2 Ashlesha Deshpande,1 Svetlana Radaeva,3 Brian A. Halloran,1 Bin Gao,3 and Mark R. Walter1,2,* 1Department of Microbiology 2Center for Biophysical Sciences and Engineering University of Alabama at Birmingham, Birmingham, AL 35294, USA 3Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA 4Present address: Department of Molecular Biology, BCC-206, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA *Correspondence: [email protected] DOI 10.1016/j.str.2010.02.009 SUMMARY pard et al., 2003) heterodimers that are activated by IL-22, IL-26, and IL-28/ IL-29, respectively (see Figure S1 available IL-10R2 is a shared cell surface receptor required online). Thus, IL-10R2 functions as a common signaling chain for the activation of five class 2 cytokines (IL-10, in the class 2 cytokine family, as observed for gp130, IL-2gc IL-22, IL-26, IL-28, and IL-29) that play critical roles (gc), and GM-CSF bc chains in the class 1 cytokine family in host defense. To define the molecular mechanisms (Wang et al., 2009). that regulate its promiscuous binding, we have Cytokines that signal via IL-10R2 induce pleiotropic activities determined the crystal structure of the IL-10R2 ecto- that protect the host from overexuberant immune responses and activate innate immunity programs in epithelial cells.
    [Show full text]
  • Tumor Invasion in Draining Lymph Nodes Is Associated with Treg Accumulation in Breast Cancer Patients
    ARTICLE https://doi.org/10.1038/s41467-020-17046-2 OPEN Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients Nicolas Gonzalo Núñez 1,7,9, Jimena Tosello Boari 1,9, Rodrigo Nalio Ramos 1, Wilfrid Richer1, Nicolas Cagnard2, Cyrill Dimitri Anderfuhren 3, Leticia Laura Niborski1, Jeremy Bigot1, Didier Meseure4,5, Philippe De La Rochere1, Maud Milder4,5, Sophie Viel1, Delphine Loirat1,5,6, Louis Pérol1, Anne Vincent-Salomon4,5, Xavier Sastre-Garau4,8, Becher Burkhard 3, Christine Sedlik 1,5, ✉ Olivier Lantz 1,4,5, Sebastian Amigorena1,5 & Eliane Piaggio 1,5 1234567890():,; Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic sig- nature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy.
    [Show full text]
  • Direct Estimation of Differential Networks
    Biometrika (2013), xx, x, pp. 1–16 C 2013 Biometrika Trust Advance Access publication on dd mm year Printed in Great Britain Direct estimation of differential networks BY SIHAI DAVE ZHAO Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA [email protected] 5 T. TONY CAI Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [email protected] HONGZHE LI 10 Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA [email protected] SUMMARY It is often of interest to understand how the structure of a genetic network differs between 15 two conditions. In this paper, each condition-specific network is modeled using the precision matrix of a multivariate normal random vector, and a method is proposed to directly estimate the difference of the precision matrices. In contrast to other approaches, such as separate or joint estimation of the individual matrices, direct estimation does not require those matrices to be sparse, and thus can allow the individual networks to contain hub nodes. Under the assumption 20 that the true differential network is sparse, the direct estimator is shown to be consistent in support recovery and estimation. It is also shown to outperform existing methods in simulations, and its properties are illustrated on gene expression data from late-stage ovarian cancer patients. Some key words: Differential network; Graphical model; High dimensionality; Precision matrix 1. INTRODUCTION 25 A complete understanding of the molecular basis of disease will require characterization of the network of interdependencies between genetic components.
    [Show full text]
  • A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member APRIL, Inhibits Tumor Cell Growth
    Brief Definitive Report A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member APRIL, Inhibits Tumor Cell Growth By Paul Rennert,‡ Pascal Schneider,* Teresa G. Cachero,‡ Jeffrey Thompson,‡ Luciana Trabach,‡ Sylvie Hertig,* Nils Holler,* Fang Qian,‡ Colleen Mullen,‡ Kathy Strauch,‡ Jeffrey L. Browning,‡ Christine Ambrose,‡ and Jürg Tschopp* From the *Institute of Biochemistry, BIL Biomedical Research Center, University of Lausanne, CH-1066 Epalinges, Switzerland; and the ‡Departments of Molecular Genetics, Immunology, Inflammation, Cell Biology, and Protein Engineering, Biogen, Incorporated, Cambridge, Massachusetts 02142 Abstract A proliferation-inducing ligand (APRIL) is a ligand of the tumor necrosis factor (TNF) family that stimulates tumor cell growth in vitro and in vivo. Expression of APRIL is highly upregu- lated in many tumors including colon and prostate carcinomas. Here we identify B cell matura- tion antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI), two predicted members of the TNF receptor family, as re- ceptors for APRIL. APRIL binds BCMA with higher affinity than TACI. A soluble form of BCMA, which inhibits the proliferative activity of APRIL in vitro, decreases tumor cell prolif- eration in nude mice. Growth of HT29 colon carcinoma cells is blocked when mice are treated once per week with the soluble receptor. These results suggest an important role for APRIL in tumorigenesis and point towards a novel anticancer strategy. Key words: tumor necrosis factor • tumorigenesis • cell survival • apoptosis • cancer therapy Introduction TNF-related ligands can induce pleiotropic biological re- tumorigenesis. APRIL is a close sequence homologue of B sponses.
    [Show full text]