DOCSLIB.ORG

Tumor Necrosis Factor and Lymphotoxin in Regulation of Intestinal Inflammation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tumor Necrosis Factor and Lymphotoxin in Regulation of Intestinal Inflammation ISSN 0006-2979, Biochemistry (Moscow), 2016, Vol. 81, No. 11, pp. 1309-1325. © Pleiades Publishing, Ltd., 2016. Original Russian Text © E. О. Gubernatorova, A. V. Tumanov, 2016, published in Biokhimiya, 2016, Vol. 81, No. 11, pp. 1559-1577. REVIEW Tumor Necrosis Factor and Lymphotoxin in Regulation of Intestinal Inflammation E. О. Gubernatorova1 and A. V. Tumanov1,2* 1Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; E-mail: [email protected] 2University of Texas Health Science Center, Department of Microbiology, Immunology, and Molecular Genetics, San Antonio, TX 78229, USA Received July 3, 2016 Revision received August 16, 2016 Abstract—Ulcerative colitis and Crohn’s disease are the major forms of inflammatory bowel disease. Cytokines of the tumor necrosis factor (TNF) family play an important role in the regulation of intestinal inflammation. In this review, we discuss the function of key cytokines of this family – TNF and lymphotoxin (LT) – in mucosal healing, IgA production, and in control of innate lymphoid cells (ILCs), novel regulators of mucosal homeostasis in the gut. TNF plays a central role in the pathogenesis of inflammatory bowel diseases (IBD). LT regulates group 3 of ILCs and IL-22 production and protects the epithelium against damage by chemicals and mucosal bacterial pathogens. In addition, we discuss major mouse models employed to study the mechanism of intestinal inflammation, their advantages and limitations, as well as application of TNF blockers in the therapy for IBD. DOI: 10.1134/S0006297916110092 Key words: tumor necrosis factor, lymphotoxin, intestinal inflammation, inflammatory bowel disease, mouse models CYTOKINES OF TNF SUPERFAMILY pairs) are expressed by immune system cells [1]. Some receptors belonging to this cytokine family, for instance, Tumor Necrosis Factor (TNF), lymphotoxin (LT), TNFR1, are able to activate mechanisms of cell death, and LIGHT (homologous to lymphotoxin, exhibits whereas others (LTβR) predominantly promote cell sur- inducible expression and competes with HSV glycopro- vival and inflammation [2]. Most ligands of the TNF tein D for binding to herpesvirus entry mediator, a recep- superfamily are membrane-associated trimeric mole- tor expressed on T-lymphocytes, TNFSF14) are key cules. However, upon activation of certain metallopro- cytokines of the TNF superfamily that perform various teinases, trimers may be converted into soluble form. For functions in mammalian biology. Most ligands and recep- instance, metalloproteinase TACE (TNF-alpha convert- tors of the TNF superfamily (over 40 ligand–receptor ing enzyme) releases the extracellular TNF moiety [3]. Intracellular parts of receptors do not contain kinase domains and are unable to bind tyrosine kinase. Thus, Abbreviations: CD, Crohn’s disease; DCs, dendritic cells; DSS, dextran sulfate sodium; FDA, Food and Drug Administration signaling is realized by means of adapter molecules. of USA; FDC, follicular dendritic cells; GALT, gut-associated Several receptors of the TNF family, such as TNFR1 and lymphoid tissue; IBD, inflammatory bowel disease; IFN, inter- Fas, contain death domains within their cytoplasmic feron; IL, interleukin; ILCs, innate lymphoid cells; LIGHT, regions, which are able to activate and recruit caspase homologous to lymphotoxin, exhibits inducible expression and precursors and to induce apoptosis. Another feature of competes with HSV glycoprotein D for binding to herpesvirus these molecules is their composition of three subunits entry mediator, a receptor expressed on T-lymphocytes (anoth- that determines signaling stereochemistry. Thus, the list- er name: tumor necrosis factor superfamily member 14, ed unique structural attributes determine the connection TNFSF14); LT, lymphotoxin; LT R, membrane lymphotoxin β between cytokines of the TNF superfamily and signal receptor; MHC, major histocompatibility complex; MNP, mononuclear phagocytes; TACE, TNF-alpha converting transduction pathways in cell proliferation, differentia- enzyme; TNBS, 2,4,6-trinitrobenzenesulfonic acid; TNF, tion, and survival [1, 2]. This is why possible use of tumor necrosis factor; TNFR, tumor necrosis factor receptor; cytokines of the TNF superfamily and their inhibitors in UC, ulcerative colitis. therapy for various autoimmune diseases and cancer is * To whom correspondence should be addressed. actively studied in recent years [4]. 1309 1310 GUBERNATOROVA, TUMANOV The main ligand–receptor interactions in the macrophages, NK cells, and DCs, can also interact with TNF/LT system as well as producer and responding cells LTβR [3]. In addition to LTβR, LIGHT can interact with are presented in the Fig. 1. TNF and TNFR are widely herpes virus entry mediator (HVEM) receptor, which is produced. Membrane lymphotoxin is an LTβ2LTα1 het- also a ligand for receptors belonging to another cytokine erotrimer that is predominantly located on lymphocytes. family, CD160 and BTLA (B and T lymphocyte attenua- LTβR receptor for the membrane lymphotoxin, in turn, is tor) [9]. This complex system of ligands and receptors in expressed in epithelial and stromal cells, dendritic cells the TNF cytokine family provides selectivity of interac- (DCs), and macrophages, but it is absent on lymphocytes tion and signal transduction between various immune sys- [3, 5]. This expression pattern for LT and LTβR provides tem cells and implies involvement of compensatory interaction of LT-producing lymphocytes – cells with mechanisms. stromal microenvironment – that is important for lymph The best-studied function of LT and LTβR is their node development and maintenance of lymphoid organ participation in lymphoid organ development, such as structure [3, 6]. Recent studies have demonstrated that lymph nodes and Peyer’s patches, and in maintenance of LTα1β2 has two LTβR binding sites with different affini- proper spleen white pulp architecture [6, 10]. However, it ties, and LTβR dimerizes upon LTα1β2 binding. This was later shown that LT function is broader and not dimerization is required for efficient signal transduction restricted to lymphoid organs and protection against [7]. Soluble LTα3 homotrimer does not bind LTβR, but it infections. Thus, it was found that LT plays an important interacts with TNFR1 and TNFR2, and, similarly to role in maintenance of lipid homeostasis and liver regen- TNF, it is able to stimulate development of various eration. It also regulates inflammation and commensal inflammatory reactions. In contrast to TNFR1, which is gut microbiota, proliferation, and tumor transformation constantly expressed in all cells, TNFR2 expression is [11-17]. In addition to maintenance of lymphoid organ more selective and inducible [8]. It is known that mem- structure, TNF also participates in defense against infec- brane TNF has higher affinity for TNFR2 compared to tions, regulation of inflammation, and autoimmune dis- the soluble TNF [8]. Another TNF family ligand, eases [18-20]. Therefore, LT, TNF, and LIGHT form an LIGHT (TNFSF14), mainly expressed on T cells, integral signaling network that is required for efficient innate and adaptive immune responses. We will further review mechanisms of TNF and LT participation in regu- Global T-, B-, NK-cells, ILC – T cells, DC, expression innate lymphoid cells macrophages lation of intestinal homeostasis and describe mouse mod- els widely used in studying the mechanisms of intestinal inflammation. EXPERIMENTAL ANIMAL MODELS FOR INTESTINAL INFLAMMATION The intestine is a sophisticated organ containing dif- ferent cell types that contact the “outer” environment and are constantly interacting with commensal microbio- ta. Revealing mechanisms involved in intestinal inflam- mation and damage is an important step in developing therapeutic strategies and prevention of disease. It is beyond doubt that the most reliable data can only be obtained during analysis of samples from patients who suffer from various diseases. However, sampling size, eth- ical issues related to utilization of human samples, and Global Epithelial and stromal cells, DC, T cells, genetic heterogeneity in the group significantly restrict expression DC, monocytes epithelial cells, macrophages human research trials. Therefore, studying pathogenesis Inflammation Modification of the gastrointestinal tract requires developing complex and activation of lymphoid T cell survival of immune microenvironment, experimental models on animals that are devoid of such system DC maturation drawbacks as sampling limitation and genetic hetero- geneity. At the same time, human diseases should be Fig. 1. Ligands and receptors of the TNF/LT family. The main lig- reproduced in these animals with maximum likeness [21- and–receptor interactions and producer cells are indicated with 23]. Advantages in the genetic engineering field and well- arrows. The dashed line indicates action sites for metallopro- teinases (MMP), whose activity converts membrane-bound ligand studied genome make mice the most-used object in mod- into a soluble form. DcR3 is a receptor-trap for LIGHT (found in eling immune processes, including those involved in some human tumors). intestinal inflammation [24]. Modeling disorders in mice BIOCHEMISTRY (Moscow) Vol. 81 No. 11 2016 TNF AND LT CYTOKINES IN REGULATION OF INTESTINAL INFLAMMATION 1311 gives a number of advantages, such as simplicity of trols in the same cage is recommended. If this is impossi- genome and microbiome manipulations, and fast genera- ble, microbiota composition is balanced before the exper- tion change.
Load more

Recommended publications
  • TNF Decoy Receptors Encoded by Poxviruses
    pathogens Review TNF Decoy Receptors Encoded by Poxviruses Francisco Javier Alvarez-de Miranda † , Isabel Alonso-Sánchez † , Antonio Alcamí and Bruno Hernaez * Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049 Madrid, Spain; [email protected] (F.J.A.-d.M.); [email protected] (I.A.-S.); [email protected] (A.A.) * Correspondence: [email protected]; Tel.: +34-911-196-4590 † These authors contributed equally. Abstract: Tumour necrosis factor (TNF) is an inflammatory cytokine produced in response to viral infections that promotes the recruitment and activation of leukocytes to sites of infection. This TNF- based host response is essential to limit virus spreading, thus poxviruses have evolutionarily adopted diverse molecular mechanisms to counteract TNF antiviral action. These include the expression of poxvirus-encoded soluble receptors or proteins able to bind and neutralize TNF and other members of the TNF ligand superfamily, acting as decoy receptors. This article reviews in detail the various TNF decoy receptors identified to date in the genomes from different poxvirus species, with a special focus on their impact on poxvirus pathogenesis and their potential use as therapeutic molecules. Keywords: poxvirus; immune evasion; tumour necrosis factor; tumour necrosis factor receptors; lymphotoxin; inflammation; cytokines; secreted decoy receptors; vaccinia virus; ectromelia virus; cowpox virus Citation: Alvarez-de Miranda, F.J.; Alonso-Sánchez, I.; Alcamí, A.; 1. TNF Biology Hernaez, B. TNF Decoy Receptors TNF is a potent pro-inflammatory cytokine with a broad range of biological effects, Encoded by Poxviruses. Pathogens ranging from the activation of inflammatory gene programs to cell differentiation or 2021, 10, 1065.
    [Show full text]
  • Dimerization of Ltβr by Ltα1β2 Is Necessary and Sufficient for Signal
    Dimerization of LTβRbyLTα1β2 is necessary and sufficient for signal transduction Jawahar Sudhamsua,1, JianPing Yina,1, Eugene Y. Chiangb, Melissa A. Starovasnika, Jane L. Groganb,2, and Sarah G. Hymowitza,2 Departments of aStructural Biology and bImmunology, Genentech, Inc., South San Francisco, CA 94080 Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved October 24, 2013 (received for review June 6, 2013) Homotrimeric TNF superfamily ligands signal by inducing trimers survival in a xenogeneic human T-cell–dependent mouse model of of their cognate receptors. As a biologically active heterotrimer, graft-versus-host disease (GVHD) (11). Lymphotoxin(LT)α1β2 is unique in the TNF superfamily. How the TNFRSF members are typically activated by TNFSF-induced three unique potential receptor-binding interfaces in LTα1β2 trig- trimerization or higher order oligomerization, resulting in initiation ger signaling via LTβ Receptor (LTβR) resulting in lymphoid organ- of intracellular signaling processes including the canonical and ogenesis and propagation of inflammatory signals is poorly noncanonical NF-κB pathways (2, 3). Ligand–receptor interactions α β understood. Here we show that LT 1 2 possesses two binding induce higher order assemblies formed between adaptor motifs in sites for LTβR with distinct affinities and that dimerization of LTβR the cytoplasmic regions of the receptors such as death domains or α β fi by LT 1 2 is necessary and suf cient for signal transduction. The TRAF-binding motifs and downstream signaling components such α β β crystal structure of a complex formed by LT 1 2,LT R, and the fab as Fas-associated protein with death domain (FADD), TNFR1- fragment of an antibody that blocks LTβR activation reveals the associated protein with death domain (TRADD), and TNFR-as- lower affinity receptor-binding site.
    [Show full text]
  • The Unexpected Role of Lymphotoxin Β Receptor Signaling
    Oncogene (2010) 29, 5006–5018 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW The unexpected role of lymphotoxin b receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development MJ Wolf1, GM Seleznik1, N Zeller1,3 and M Heikenwalder1,2 1Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland and 2Institute of Virology, Technische Universita¨tMu¨nchen/Helmholtz Zentrum Mu¨nchen, Munich, Germany The cytokines lymphotoxin (LT) a, b and their receptor genesis. Consequently, the inflammatory microenviron- (LTbR) belong to the tumor necrosis factor (TNF) super- ment was added as the seventh hallmark of cancer family, whose founder—TNFa—was initially discovered (Hanahan and Weinberg, 2000; Colotta et al., 2009). due to its tumor necrotizing activity. LTbR signaling This was ultimately the result of more than 100 years of serves pleiotropic functions including the control of research—indeed—the first observation that tumors lymphoid organ development, support of efficient immune often arise at sites of inflammation was initially reported responses against pathogens due to maintenance of intact in the nineteenth century by Virchow (Balkwill and lymphoid structures, induction of tertiary lymphoid organs, Mantovani, 2001). Today, understanding the underlying liver regeneration or control of lipid homeostasis. Signal- mechanisms of why immune cells can be pro- or anti- ing through LTbR comprises the noncanonical/canonical carcinogenic in different types of tumors and which nuclear factor-jB (NF-jB) pathways thus inducing cellular and molecular inflammatory mediators (for chemokine, cytokine or adhesion molecule expression, cell example, macrophages, lymphocytes, chemokines or proliferation and cell survival.
    [Show full text]
  • Expression Il2 Differentiation by Promoting TNFR2 Impairs Th17
    Transmembrane TNF−TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression Patrick G. Miller, Michael B. Bonn and Susan C. McKarns This information is current as J Immunol 2015; 195:2633-2647; Prepublished online 12 of October 3, 2021. August 2015; doi: 10.4049/jimmunol.1500286 http://www.jimmunol.org/content/195/6/2633 Downloaded from References This article cites 76 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/195/6/2633.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 3, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Transmembrane TNF–TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression Patrick G. Miller,* Michael B. Bonn,* and Susan C. McKarns*,† The double-edged sword nature by which IL-2 regulates autoimmunity and the unpredictable outcomes of anti-TNF therapy in autoimmunity highlight the importance for understanding how TNF regulates IL-2.
    [Show full text]
  • Targeting and Utilizing Primary Tumors As Live Vaccines: Changing Strategies
    Cellular & Molecular Immunology (2012) 9, 20–26 ß 2012 CSI and USTC. All rights reserved 1672-7681/12 $32.00 www.nature.com/cmi REVIEW Targeting and utilizing primary tumors as live vaccines: changing strategies Xuanming Yang, Eric D Mortenson and Yang-Xin Fu Tumor metastases and relapse are the major causes of morbidity and mortality in cancer. Although surgery, chemotherapy and/or radiation therapy can typically control primary tumor growth, metastatic and relapsing tumors are often inaccessible or resistant to these treatments. An adaptive immune response can be generated during these conventional treatments of the primary tumor, and presumably both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system. Thus, when established, this response should be able to control metastatic growth and tumor relapse. This review summarizes the mechanisms by which antitumor immune responses are generated, and recent findings supporting the hypothesis that many therapies targeting primary tumors can generate antitumor adaptive immune responses to prevent metastases and tumor relapse. Cellular & Molecular Immunology (2012) 9, 20–26; doi:10.1038/cmi.2011.49; published online 21 November 2011 Keywords: chemotherapy; immunotherapy; metastasis; radiotherapy; tumor vaccine INTRODUCTION tissues.3–5 Thus, overcoming tumor-associated immune-suppressive Conventional treatments such as surgery and chemotherapy are effec- mechanisms to induce potent antitumor immunity is the first step for tive means of eliminating or reducing primary tumor growth, but have effective cancer immunotherapy.5–7 Many mechanisms are involved not proved effective in eradicating metastases. Because metastatic dis- in tumor-associated immune suppression of naive and previously ease may not respond similarly to chemotherapies used in treating the activated T cells.
    [Show full text]
  • Targeting Lymphotoxin Beta and Paired Box 5: a Potential
    Huang et al. Cancer Cell Int (2021) 21:3 https://doi.org/10.1186/s12935-020-01632-x Cancer Cell International PRIMARY RESEARCH Open Access Targeting Lymphotoxin Beta and Paired Box 5: a potential therapeutic strategy for soft tissue sarcoma metastasis Runzhi Huang1,2†, Zhiwei Zeng1†, Penghui Yan1†, Huabin Yin3, Xiaolong Zhu1, Peng Hu1, Juanwei Zhuang1, Jiaju Li1, Siqi Li4, Dianwen Song3*, Tong Meng2,3* and Zongqiang Huang1*† Abstract Background: Soft tissue sarcomas (STS) has a high rate of early metastasis. In this study, we aimed to uncover the potential metastasis mechanisms and related signaling pathways in STS with diferentially expressed genes and tumor-infltrating cells. Methods: RNA-sequencing (RNA-seq) of 261 STS samples downloaded from the Cancer Genome Atlas (TCGA) database were used to identify metastasis-related diferentially expressed immune genes and transcription factors (TFs), whose relationship was constructed by Pearson correlation analysis. Metastasis-related prediction model was established based on the most signifcant immune genes. CIBERSORT algorithm was performed to identify signifcant immune cells co-expressed with key immune genes. The GSVA and GSEA were performed to identify prognosis- related KEGG pathways. Ultimately, we used the Pearson correlation analysis to explore the relationship among immune genes, immune cells, and KEGG pathways. Additionally, key genes and regulatory mechanisms were vali- dated by single-cell RNA sequencing and ChIP sequencing data. Results: A total of 204 immune genes and 12 TFs, were identifed. The prediction model achieved a satisfactory efec- tiveness in distant metastasis with the Area Under Curve (AUC) of 0.808. LTB was signifcantly correlated with PAX5 (P < 0.001, R 0.829) and hematopoietic cell lineage pathway (P < 0.001, R 0.375).
    [Show full text]
  • The Expression of Genes Contributing to Pancreatic Adenocarcinoma Progression Is Influenced by the Respective Environment – Sagini Et Al
    The expression of genes contributing to pancreatic adenocarcinoma progression is influenced by the respective environment – Sagini et al Supplementary Figure 1: Target genes regulated by TGM2. Figure represents 24 genes regulated by TGM2, which were obtained from Ingenuity Pathway Analysis. As indicated, 9 genes (marked red) are down-regulated by TGM2. On the contrary, 15 genes (marked red) are up-regulated by TGM2. Supplementary Table 1: Functional annotations of genes from Suit2-007 cells growing in pancreatic environment Categoriesa Diseases or p-Valuec Predicted Activation Number of genesf Functions activationd Z-scoree Annotationb Cell movement Cell movement 1,56E-11 increased 2,199 LAMB3, CEACAM6, CCL20, AGR2, MUC1, CXCL1, LAMA3, LCN2, COL17A1, CXCL8, AIF1, MMP7, CEMIP, JUP, SOD2, S100A4, PDGFA, NDRG1, SGK1, IGFBP3, DDR1, IL1A, CDKN1A, NREP, SEMA3E SERPINA3, SDC4, ALPP, CX3CL1, NFKBIA, ANXA3, CDH1, CDCP1, CRYAB, TUBB2B, FOXQ1, SLPI, F3, GRINA, ITGA2, ARPIN/C15orf38- AP3S2, SPTLC1, IL10, TSC22D3, LAMC2, TCAF1, CDH3, MX1, LEP, ZC3H12A, PMP22, IL32, FAM83H, EFNA1, PATJ, CEBPB, SERPINA5, PTK6, EPHB6, JUND, TNFSF14, ERBB3, TNFRSF25, FCAR, CXCL16, HLA-A, CEACAM1, FAT1, AHR, CSF2RA, CLDN7, MAPK13, FERMT1, TCAF2, MST1R, CD99, PTP4A2, PHLDA1, DEFB1, RHOB, TNFSF15, CD44, CSF2, SERPINB5, TGM2, SRC, ITGA6, TNC, HNRNPA2B1, RHOD, SKI, KISS1, TACSTD2, GNAI2, CXCL2, NFKB2, TAGLN2, TNF, CD74, PTPRK, STAT3, ARHGAP21, VEGFA, MYH9, SAA1, F11R, PDCD4, IQGAP1, DCN, MAPK8IP3, STC1, ADAM15, LTBP2, HOOK1, CST3, EPHA1, TIMP2, LPAR2, CORO1A, CLDN3, MYO1C,
    [Show full text]
  • Human Colon Cancer Primer Library
    Human Colon Cancer Primer Library Catalog No: HCCR-1 Supplier: RealTimePrimers Lot No: XXXXX Supplied as: solid Stability: store at -20°C Description Contains 88 primer sets directed against cytokine and chemokine receptor genes and 8 housekeeping gene primer sets. Provided in a 96-well microplate (20 ul - 10 uM). Perform up to 100 PCR arrays (based on 20 ul assay volume per reaction). Just add cDNA template and SYBR green master mix. Gene List: • CCR1 chemokine (C-C motif) receptor 1 • IL11RA interleukin 11 receptor, alpha • CCR2 chemokine (C-C motif) receptor 2 • IL11RB interleukin 11 receptor, beta • CCR3 chemokine (C-C motif) receptor 3 • IL12RB1 interleukin 12 receptor, beta 1 • CCR4 chemokine (C-C motif) receptor 4 • IL12RB2 interleukin 12 receptor, beta 2 • CCR5 chemokine (C-C motif) receptor 5 • IL13RA1 interleukin 13 receptor, alpha 1 • CCR6 chemokine (C-C motif) receptor 6 • IL13RA2 interleukin 13 receptor, alpha 2 • CCR7 chemokine (C-C motif) receptor 7 • IL15RA interleukin 15 receptor, alpha • CCR8 chemokine (C-C motif) receptor 8 • IL15RB interleukin 15 receptor, beta • CCR9 chemokine (C-C motif) receptor 9 • IL17RA interleukin 17 receptor A • CCR10 chemokine (C-C motif) receptor 10 • IL17RB interleukin 17 receptor B • CX3CR1 chemokine (C-X3-C motif) receptor 1 • IL17RC interleukin 17 receptor C • CXCR1 chemokine (C-X-C motif) receptor 1 • IL17RD interleukin 17 receptor D • CXCR2 chemokine (C-X-C motif) receptor 2 • IL17RE interleukin 17 receptor E • CXCR3 chemokine (C-X-C motif) receptor 3 • IL18R1 interleukin 18 receptor
    [Show full text]
  • Dual Role of TNF and Ltα in Carcinogenesis As Implicated by Studies in Mice
    cancers Review Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice Ekaterina O. Gubernatorova 1,2,*, Almina I. Polinova 1,2, Mikhail M. Petropavlovskiy 1,2, Olga A. Namakanova 1,2, Alexandra D. Medvedovskaya 1,2, Ruslan V. Zvartsev 1,3, Georgij B. Telegin 4, Marina S. Drutskaya 1,3,* and Sergei A. Nedospasov 1,2,3,5,* 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; [email protected] (A.I.P.); [email protected] (M.M.P.); [email protected] (O.A.N.); [email protected] (A.D.M.); [email protected] (R.V.Z.) 2 Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia 3 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia 4 Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences (BIBCh, RAS), 142290 Pushchino, Russia; [email protected] 5 Sirius University of Science and Technology, Federal Territory Sirius, 354340 Krasnodarsky Krai, Russia * Correspondence: [email protected] (E.O.G.); [email protected] (M.S.D.); [email protected] (S.A.N.) Simple Summary: Tumor necrosis factor (TNF) and its closely related cytokine, lymphotoxin alpha (LTα), are part of the TNF superfamily and exert their functions via both overlapping and non- Citation: Gubernatorova, E.O.; redundant signaling pathways. Reported pro- and antitumorigenic effects of TNF and lymphotoxin Polinova, A.I.; Petropavlovskiy, M.M.; are often context-dependent and may be contingent on a particular experimental approach, such Namakanova, O.A.; Medvedovskaya, as transplantable and chemically induced tumor models; tissue and organ specificity; types of cells A.D.; Zvartsev, R.V.; Telegin, G.B.; producing these cytokines or responding to them; and the genotype and genetic background of mice.
    [Show full text]
  • Lymphotoxin Α Revisited: General Features and Implications in Rheumatoid Arthritis
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Calmon-Hamaty et al. Arthritis Research & Therapy 2011, 13:232 http://arthritis-research.com/content/13/4/232 REVIEW Lymphotoxin α revisited: general features and implications in rheumatoid arthritis Flavia Calmon-Hamaty1, Bernard Combe1-3, Michael Hahne1,4 and Jacques Morel*1-3 strategies in order to better control synovial infl ammation Abstract and joint destruction observed in RA. Although lympho- Rheumatoid arthritis (RA) is a chronic infl ammatory toxin alpha (LTα) has been associated with autoimmune disease aff ecting synovial joints. Therapies blocking and infl ammatory diseases and is the closest homolog to tumor necrosis factor-alpha (TNFα) are now routinely TNFα, few data pointing to a role for LTα in RA are used in the management of RA. However, a signifi cant available [4-10]. In this review, we aim to summarize the number of patients with RA do not respond or general features of LTα and what at present is known develop resistance to anti-TNF therapies, and the about its role in RA. participation of other cytokines in RA pathogenesis has been reported as well. Lymphotoxin alpha (LTα) is Lymphotoxin alpha in general the closest homolog to TNFα and has been implicated LTα, formerly known as TNFβ, was originally described in infl ammation and autoimmunity since its original in 1968 as a cytotoxic factor produced by T lymphocytes description in 1968. In spite of that, little is known after antigenic or mitogenic stimulation [11]. Later on, in about the role of LTα in RA or the potential of blocking 1984, human LTα was purifi ed from a B-lymphoblastoid this cytokine as an alternative therapeutic approach.
    [Show full text]
  • Recombinant Mouse Lymphotoxin Α1/Β2 Catalog Number: 9968-LY/CF
    Recombinant Mouse Lymphotoxin α1/β2 Catalog Number: 9968-LY/CF DESCRIPTION Source Mouse myeloma cell line, NS0­derived mouse Lymphotoxin protein Mouse LT alpha Mouse LT beta Mouse LT beta (Lys59­Leu202) GGGGS (Leu153­Gly306) GGGGS (Leu153­Gly306) Accession # P09225 Accession # P41155 Accession # P41155 N­terminal Sequence Lys59 Analysis Structure / Form GS­linked heterotrimer Predicted Molecular 50 kDa Mass SPECIFICATIONS SDS­PAGE 42­63 kDa, reducing conditions Activity Measured in a cell proliferation assay using NIH­3T3 mouse embryonic fibroblast cells. The ED50 for this effect is 0.3­2.1 ng/mL Endotoxin Level <0.10 EU per 1 μg of the protein by the LAL method. Purity >95%, by SDS­PAGE visualized with Silver Staining and quantitative densitometry by Coomassie® Blue Staining. Formulation Lyophilized from a 0.2 μm filtered solution in PBS. See Certificate of Analysis for details. PREPARATION AND STORAGE Reconstitution Reconstitute at 500 μg/mL in PBS. Shipping The product is shipped at ambient temperature. Upon receipt, store it immediately at the temperature recommended below. Stability & Storage l 12 months from date of receipt, ≤ ­20 °C as supplied. l 1 month, 2 to 8 °C under sterile conditions after reconstitution. l 3 months, ≤ ­20 °C under sterile conditions after reconstitution. DATA Bioactivity SDS­PAGE Recombinant Mouse 2 μg/lane of Recombinant Mouse Lymphotoxin alpha1/beta2 Lymphotoxin α1/β2 was resolved with SDS­PAGE under reducing (R) and non­ (Catalog # 9968­ reducing (NR) conditions and visualized by Coomassie® blue LY/CF) induces NIH­ staining, showing bands at 42­63 kDa. 3T3 mouse embryonic fibroblast cell proliferation.
    [Show full text]
  • Blockade of LIGHT/Ltβ and CD40 Signaling Induces Allospecific T Cell Anergy, Preventing Graft-Versus-Host Disease
    Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease Koji Tamada, … , Bruce R. Blazar, Lieping Chen J Clin Invest. 2002;109(4):549-557. https://doi.org/10.1172/JCI13604. Article Previous studies have shown that blockade of LIGHT, a T cell costimulatory molecule belonging to the TNF superfamily, by soluble lymphotoxin β receptor–Ig (LTβR-Ig) inhibits the cytotoxic T lymphocyte (CTL) response to host antigenic disparities and ameliorates lethal graft-versus-host disease (GVHD) in a B6 to BDF1 mouse model. Here, we demonstrate that infusion of an mAb against CD40 ligand (CD40L) further increases the efficacy of LTβR-Ig, leading to complete prevention of GVHD. We further demonstrate that alloantigen-specific CTLs become anergic upon rapid expansion, and persist in the tolerized mice as a result of costimulatory blockade. Transfer of anergic CTLs to secondary F1 mice fails to induce GVHD despite the fact that anergic CTLs can be stimulated to proliferate in vitro by antigens and cytokines. Our study provides a potential new approach for the prevention of lethal GVHD. Find the latest version: https://jci.me/13604/pdf Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease Koji Tamada,1 Hideto Tamura,1 Dallas Flies,1 Yang-Xin Fu,2 Esteban Celis,1 Larry R. Pease,1 Bruce R. Blazar,3 and Lieping Chen1 1Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA 2Department of Pathology, University of Chicago, Chicago, Illinois, USA 3Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA Address correspondence to: Lieping Chen, Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
    [Show full text]