DOCSLIB.ORG

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, Or Reduce?

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, Or Reduce? Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce? Carine Savarin-Vuaillat* and Richard M. Ransohoff*† *Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, and †Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Summary: Chemokines and chemokine receptors comprise a specific expression in A␤ plaques, may be a marker for Alzheimer large number of molecules implicated in a wide range of physio- pathology. Downregulation of CCL2 in cerebrospinal fluid may be logical and pathological functions. Numerous studies have dem- a candidate to characterize multiple sclerosis (MS), but needs onstrated the roles of chemokines and chemokine receptors: 1) additional investigation. Moreover, chemokines and chemokine during development, by regulating hematopoiesis, cardiogenesis, receptors represent interesting therapeutic targets. Using chemo- and vascular and cerebellar development; 2) during tumor biology, kine receptor antagonists, several studies provided exciting find- by controlling cell proliferation, angiogenesis, and metastasis; and ings for potential neurological disease treatment. Chemokine re- 3), especially during leukocyte migration, by acting on firm ad- ceptor antagonists reduce disease severity in animal models of hesion, locomotion, diapedesis, and chemotaxis. This review fo- MS. In glioblastoma, a CXCR4 antagonist (AMD3100) showed cuses on chemokine and chemokine receptor involvement in di- an inhibition of tumor growth. Inhibition of chemokine recep- verse neurological diseases and their therapeutic potentials. tor signaling is not the only therapeutic strategy: for exam- Because of its induction or upregulation during CNS pathologies, ple, CXCR4–CXCL12 has anti-inflammatory properties and members of the chemokine system can be used as biological CX3CL1–CX3CR1 controls neurotoxicity. Thus, chemokine markers. CXCR4 and CXCL12, by the correlation between their biology suggests several approaches for treating neurologi- expression and the glioblastoma tumor progression, could be a cal disease. Key Words: Chemokines, chemokine receptors, marker to grade this type of CNS tumor. CCR1, by virtue of neurological disease, cell trafficking, marker, antagonist. INTRODUCTION kine receptors have been described. Chemokine recep- tors are defined by selective, high-affinity ligand binding Chemokines—the term is a contraction of chemotactic coupled with demonstrable biological activity (usually cytokines—comprise a large family of small (8–14 kDa) chemotaxis or calcium mobilization). basic proteins that display a wide variety of biological and pathological functions. In vitro, the signature assay for chemokines involves stimulation of leukocyte che- Chemokines motaxis in a concentration-dependent manner. The first The complexity of the chemokine family is due to the chemokine to be described was IL8 (CXCL8), identified large number of component molecules. Moreover, add- in 1987 as a molecule with selective neutrophil chemoat- ing confusion to complexity, rapid discovery of new tractant properties.1 Since then, the chemokine family chemokines resulted in various research groups calling steadily expanded, now including more than 50 mole- the same molecule by different names. This unmanage- cules. Chemokines act by binding to G-protein-coupled able situation motivated a consortium, at the Keystone Symposium on Chemokine and Chemokine Receptors in cell-surface receptors on target cells. The first chemokine 3 receptor (IL8–CXCL8 receptor) was discovered in 1999, to create a systematic nomenclature. 1991.2 In parallel with their ligands, the interest in che- Chemokines are classified into four subfamilies ac- mokine receptors has grown and now nearly 20 chemo- cording to the configuration of two positionally con- served cysteine residues near the NH2 terminus. These include the CXC; CC; C; and CX3C subfamilies4,5 (FIG. 1)(http://cytokine.medic.kumamoto-u.ac.jp/CFC/CK/ Address correspondence and reprint requests to: Richard M. Ranso- hoff, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail: Chemokine.html). [email protected]. The CXC and CC chemokines are the two major sub- 590 Vol. 4, 590–601, October 2007 © The American Society for Experimental NeuroTherapeutics, Inc. CHEMOKINE BIOLOGY IN NEUROLOGICAL DISEASE 591 FIG. 1. Chemokine nomenclature. Neurotherapeutics, Vol. 4, No. 4, 2007 592 SAVARIN-VUAILLAT AND RANSOHOFF families. The largest consists of CC chemokines, which Chemokine receptors are characterized by the adjacent position of the first two Chemokines exert their biological functions by binding to cysteine residues. CC subfamily members have a large seven-transmembrane-domain G-protein-coupled receptors spectrum of action and can attract monocytes, eosino- on target cells. The chemokine and chemokine receptor phils, basophils, T lymphocytes, natural killer (NK) nomenclatures are correlated, in that receptors that bind CC cells, and dendritic cells. This heterogeneity also extends chemokines (for example) are termed CC, followed by ‘R’ to their protein sequences and chromosome localization for receptor and a number that denotes the order of cloning. which allow for an informal categorization of this sub- Thus, the chemokine receptor family comprises the CC family into various groups, including allergenic (or (CCR1–10), CXC (CXCR1–7), XCR1 and CX3CR1 recep- MCP–eotaxin), inflammatory, HCC (hemofiltrate CC tors (FIG. 2). Chemokine specificity is largely restricted to receptors belonging to the same subgroup. In each sub- chemokine), developmental, and homeostatic sub- group, however, individual chemokines can bind more than groups.5 The MCP–eotaxin subgroup includes CCL2 one chemokine receptor just as single chemokine receptors (MCP1), the most extensively studied CC chemokine6 can be activated by diverse chemokines. There are isolated (FIG. 1). instances of monogamous chemokine–chemokine receptor The CXC chemokines are characterized by the inter- pairs: CXCL13–CXCR5, CXCL16–CXCR6, CCL1– position of a single amino acid (X) between their first CCR8, CCL25–CCR9, and CX3CL1–CX3CR19 (FIG. 2). two cysteine residues. This CXC subfamily can be sub- The expression of chemokine receptors is heteroge- classified into two other groups, depending on the pres- neous and is not restricted to hematopoietic cells. As ence or absence of the sequence motif glutamic acid– with their ligands, chemokine receptor expression can be leucine–arginine (ELR) near the N-terminus (FIG. 1). constitutive or inducible, but also downregulated by ex- This structural characteristic of CXC chemokines pro- posure to ligand or to activating and differentiating stim- vides a functional correlation: those containing the ELR uli (FIG. 3). Moreover, some chemokine receptors are motif bind and activate CXCR2, providing specificity for widely expressed, whereas others are restricted to certain neutrophils and other CXCR2-positive cells, whereas specific cells or by specific activation or differentiation those without the ELR motif have poor chemotactic abil- states.4 ity for neutrophils and act primarily on lymphocytes and The activation of chemokine receptors is induced by monocytes. the recognition and binding of their ligands. Based Unlike these two major subfamilies, the C and CX3C partly on analogy with other peptide ligands for G- chemokines contain two members and one member, re- protein-coupled receptors, the initial recognition be- spectively. The C chemokines, which comprise XCL1 tween chemokines and their receptors implicates ex- ␤ and XCL2, are distinguished from the other chemokine posed loops between the -strands of the chemokine subfamilies by the presence of only two of the four fold and the chemokine receptor extracellular protrud- 7 ing regions. Next, the N terminal region of the che- conserved cysteine residues. C chemokines can act on 10 lymphocytes, but not on neutrophils or monocytes. mokine initiates the activation of the receptor, which The sole CX3C chemokine is CX3CL1 (fractalkine). is followed by the internalization of the complex. G proteins are then activated, driving dissociation of CX3CL1 is characterized by the presence of three amino their heterotrimers into ␣ and ␤␥ subunits. Next, var- acids between the first two cysteine residues and also by ious signaling cascade effectors are activated, includ- an extended C-terminal sequence including a mucin-like ing phospholipase C (PLC), MAP kinases, or phos- domain and transmembrane and cytoplasmic regions. 11,12 phatidyl inositol-3OH kinase (PI-3K), which leads According to these structural features, CX3CL1 can be 8 to functional outcomes induced by chemokine receptor soluble as well as membrane-bound and acts as an ad- signaling (FIG. 3). hesion molecule or a chemoattractant for T cells, NK Chemokine receptor activation and signaling are cells, and mononuclear phagocytes. strictly controlled by desensitization, which prevents In parallel to this conventional nomenclature, many overstimulation of cells and inappropriate response12,13 chemokines can be broadly classified into two functional (FIG. 3). Chemokine receptor desensitization implies a groups. The first group comprises the homeostatic che- multistep process and a complex of proteins, including mokines, which are expressed constitutively and gener- G-protein-coupled receptor kinases (GRKs) and ␤-ar- ally involved in lymphoid organ development
Load more

Recommended publications
  • ENSG Gene Encodes Effector TCR Pathway Costimulation Inhibitory/Exhaustion Synapse/Adhesion Chemokines/Receptors
    ENSG Gene Encodes Effector TCR pathway Costimulation Inhibitory/exhaustion Synapse/adhesion Chemokines/receptors ENSG00000111537 IFNG IFNg x ENSG00000109471 IL2 IL-2 x ENSG00000232810 TNF TNFa x ENSG00000271503 CCL5 CCL5 x x ENSG00000139187 KLRG1 Klrg1 x ENSG00000117560 FASLG Fas ligand x ENSG00000121858 TNFSF10 TRAIL x ENSG00000134545 KLRC1 Klrc1 / NKG2A x ENSG00000213809 KLRK1 Klrk1 / NKG2D x ENSG00000188389 PDCD1 PD-1 x x ENSG00000117281 CD160 CD160 x x ENSG00000134460 IL2RA IL-2 receptor x subunit alpha ENSG00000110324 IL10RA IL-10 receptor x subunit alpha ENSG00000115604 IL18R1 IL-18 receptor 1 x ENSG00000115607 IL18RAP IL-18 receptor x accessory protein ENSG00000081985 IL12RB2 IL-12 receptor x beta 2 ENSG00000186810 CXCR3 CXCR3 x x ENSG00000005844 ITGAL CD11a x ENSG00000160255 ITGB2 CD18; Integrin x x beta-2 ENSG00000156886 ITGAD CD11d x ENSG00000140678 ITGAX; CD11c x x Integrin alpha-X ENSG00000115232 ITGA4 CD49d; Integrin x x alpha-4 ENSG00000169896 ITGAM CD11b; Integrin x x alpha-M ENSG00000138378 STAT4 Stat4 x ENSG00000115415 STAT1 Stat1 x ENSG00000170581 STAT2 Stat2 x ENSG00000126561 STAT5a Stat5a x ENSG00000162434 JAK1 Jak1 x ENSG00000100453 GZMB Granzyme B x ENSG00000145649 GZMA Granzyme A x ENSG00000180644 PRF1 Perforin 1 x ENSG00000115523 GNLY Granulysin x ENSG00000100450 GZMH Granzyme H x ENSG00000113088 GZMK Granzyme K x ENSG00000057657 PRDM1 Blimp-1 x ENSG00000073861 TBX21 T-bet x ENSG00000115738 ID2 ID2 x ENSG00000176083 ZNF683 Hobit x ENSG00000137265 IRF4 Interferon x regulatory factor 4 ENSG00000140968 IRF8 Interferon
    [Show full text]
  • Complementary DNA Microarray Analysis of Chemokines and Their Receptors in Allergic Rhinitis RX Zhang,1 SQ Yu,2 JZ Jiang,3 GJ Liu3
    RX Zhang, et al ORIGINAL ARTICLE Complementary DNA Microarray Analysis of Chemokines and Their Receptors in Allergic Rhinitis RX Zhang,1 SQ Yu,2 JZ Jiang,3 GJ Liu3 1 Department of Otolaryngology, Huadong Hospital, Fudan University, Shanghai, China 2 Department of Otolaryngology , Jinan General Hospital of PLA, Shandong, China 3 Department of Otolaryngology, Changhai Hospital, Second Military Medical University, Shanghai, China ■ Abstract Objective: To analyze the roles of chemokines and their receptors in the pathogenesis of allergic rhinitis by observing the complementary DNA (cDNA) expression of the chemokines and their receptors in the nasal mucosa of patients with and without allergic rhinitis, using gene chips. Methods: The total RNAs were isolated from the nasal mucosa of 20 allergic rhinitis patients and purifi ed to messenger RNAs, and then reversely transcribed to cDNAs and incorporated with samples of fl uorescence-labeled with Cy5-dUPT (rhinitis patient samples) or Cy3- dUTP (control samples of nonallergic nasal mucosa). Thirty-nine cDNAs of chemokines and their receptors were latticed into expression profi le chips, which were hybridized with probes and then scanned with the computer to study gene expression according to the different fl uorescence intensities. Results: The cDNAs of the following chemokines were upregulated: CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL14, CCL17, CCL18, CCL19, CCL24, and CX3CL1 in most of the allergic rhinitis sample chips. CCR2, CCR3, CCR4, CCR5, CCR8 and CX3CR1 were the highly expressed receptor genes. Low expression of CXCL4 was found in these tissues. Conclusion: The T helper cell (TH) immune system is not well regulated in allergic rhinitis.
    [Show full text]
  • Chemochine E Immunità
    Chemochine e Immunità Mariagrazia Uguccioni AIBT 2016 – Pesaro 1987 – Discovery of the first “chemotactic cytokine” – IL8 Marco Baggiolini Theodor Kocher Institute University of Bern (CH) The Chemokine System - 2016 CCL23 CXCL8 CCL15 CXCL7 CCL14 CXCL6 CCL13 CXCL5 CXCL8 CXCL3 CCL8 CXCL6 CCL7 CXCL11 CXCL2 CXCL1 CCL5 CCL13 CXCL10 CCL3 CCL8 CXCR1 CXCL9 CCL7 CCL26 CXCR2 CCR1 CCL2 CCL13 CXCR3 CCL11 CXCL12 CCR2 CCL8 CCL7 CXCR4 CCL5 CCR3 CXCL13 CXCR5 CCL22 CCL17 CCR4 CXCL16 CXCR6 CCL3 CCR5 CCL4 CXCL17 CXCR8 CCL5 CCL8 CCR6 CX3CR1 CCL20 CX3CL1 XCR1 CCR7 XCL1 CCL19 CCR10 CCR8 XCL2 CCR9 CCL21 CCL27 CCL1 CCL28 CCL25 Cell Migration Selectin-mediated rolling 1 Chemoattractan signalling 2 Integrin-mediated cell adhesion 3 Step 1: attachement and rolling Migration along Step 2: activation chemotactic gradient Step 3: arrest and adhesion Chemokine source Functional Modules in Cell Migration T naive IL-2 CCR7 mature DC Priming B naive IL-6 CXCR5 FDC, TFH Antibody immature DC GM-CSF CCR1, CCR5 T naive Antigen uptake TH1 IFN- CCR5 M Bacteria TH2 IL-4, IL-5 CCR3 Eos/Bas Parasites TH17 IL-17, IL-22 CCR6 Neut Fungi CTL IFN-, Perf CXCR3 M Virus From Blood to Tissue CCR1 Tissue Blood CCR2 CCR2 CCR5 CXCR3 From Tissue to Lymph Nodes CCL21 Lymph nodes are privileged sites normal for dendritic cell-naïve T cell encounters CCL21 CCR7 CCL21 inflamed CCL19 from S. Lira, Nat Immunol 2005, 6:866. Functional Modules in Cell Migration T naive IL-2 CCR7 mature DC Priming B naive IL-6 CXCR5 FDC, TFH Antibody immature DC GM-CSF CCR1, CCR5 T naive Antigen uptake TH1 IFN- CCR5
    [Show full text]
  • The Chemokine System in Innate Immunity
    Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press The Chemokine System in Innate Immunity Caroline L. Sokol and Andrew D. Luster Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 Correspondence: [email protected] Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. Theyalso recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses. hemokines are chemotactic cytokines that with emphasis placed on its role in the innate Ccontrol cell migration and cell positioning immune system. throughout development, homeostasis, and in- flammation. The immune system, which is de- pendent on the coordinated migration of cells, CHEMOKINES AND CHEMOKINE RECEPTORS is particularly dependent on chemokines for its function.
    [Show full text]
  • Role of Chemokines in Hepatocellular Carcinoma (Review)
    ONCOLOGY REPORTS 45: 809-823, 2021 Role of chemokines in hepatocellular carcinoma (Review) DONGDONG XUE1*, YA ZHENG2*, JUNYE WEN1, JINGZHAO HAN1, HONGFANG TUO1, YIFAN LIU1 and YANHUI PENG1 1Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, Hebei 050051; 2Medical Center Laboratory, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, P.R. China Received September 5, 2020; Accepted December 4, 2020 DOI: 10.3892/or.2020.7906 Abstract. Hepatocellular carcinoma (HCC) is a prevalent 1. Introduction malignant tumor worldwide, with an unsatisfactory prognosis, although treatments are improving. One of the main challenges Hepatocellular carcinoma (HCC) is the sixth most common for the treatment of HCC is the prevention or management type of cancer worldwide and the third leading cause of of recurrence and metastasis of HCC. It has been found that cancer-associated death (1). Most patients cannot undergo chemokines and their receptors serve a pivotal role in HCC radical surgery due to the presence of intrahepatic or distant progression. In the present review, the literature on the multi- organ metastases, and at present, the primary treatment methods factorial roles of exosomes in HCC from PubMed, Cochrane for HCC include surgery, local ablation therapy and radiation library and Embase were obtained, with a specific focus on intervention (2). These methods allow for effective treatment the functions and mechanisms of chemokines in HCC. To and management of patients with HCC during the early stages, date, >50 chemokines have been found, which can be divided with 5-year survival rates as high as 70% (3). Despite the into four families: CXC, CX3C, CC and XC, according to the continuous development of traditional treatment methods, the different positions of the conserved N-terminal cysteine resi- issue of recurrence and metastasis of HCC, causing adverse dues.
    [Show full text]
  • CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells with an Increased Cytotoxic Potential
    + CD29 identifies IFN-γ–producing human CD8 T cells with an increased cytotoxic potential Benoît P. Nicoleta,b, Aurélie Guislaina,b, Floris P. J. van Alphenc, Raquel Gomez-Eerlandd, Ton N. M. Schumacherd, Maartje van den Biggelaarc,e, and Monika C. Wolkersa,b,1 aDepartment of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands; bLandsteiner Laboratory, Oncode Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; cDepartment of Research Facilities, Sanquin Research, 1066 CX Amsterdam, The Netherlands; dDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and eDepartment of Molecular and Cellular Haemostasis, Sanquin Research, 1066 CX Amsterdam, The Netherlands Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019) Cytotoxic CD8+ T cells can effectively kill target cells by producing therefore developed a protocol that allowed for efficient iso- cytokines, chemokines, and granzymes. Expression of these effector lation of RNA and protein from fluorescence-activated cell molecules is however highly divergent, and tools that identify and sorting (FACS)-sorted fixed T cells after intracellular cytokine + preselect CD8 T cells with a cytotoxic expression profile are lacking. staining. With this top-down approach, we performed an un- + Human CD8 T cells can be divided into IFN-γ– and IL-2–producing biased RNA-sequencing (RNA-seq) and mass spectrometry cells. Unbiased transcriptomics and proteomics analysis on cytokine- γ– – + + (MS) analyses on IFN- and IL-2 producing primary human producing fixed CD8 T cells revealed that IL-2 cells produce helper + + + CD8 Tcells.
    [Show full text]
  • Chemokines and Their Receptors in Rheumatoid Arthritis
    ARTHRITIS & RHEUMATISM Vol. 52, No. 3, March 2005, pp 710–721 DOI 10.1002/art.20932 © 2005, American College of Rheumatology REVIEW Chemokines and Their Receptors in Rheumatoid Arthritis Future Targets? Alisa E. Koch Introduction tem was introduced in 2000, in which chemokines are considered as chemokine ligands, and each chemokine Rheumatoid arthritis (RA) is a chronic inflam- has been assigned a designation of CXCL, CCL, XCL, matory disease leading to joint destruction (1). In RA, or CX3CL1 (Figure 1) (10–12). In this report, both the migration of leukocytes into the synovial tissue (ST) former and new nomenclature are noted. occurs. These leukocytes and other cells in the ST, particularly RA ST fibroblasts, produce mediators of CXC chemokines have 2 conserved cysteines inflammation, including chemokines (1). Chemokines, separated by 1 unconserved amino acid (9,13) (Figure currently numbering more than 50, are chemotactic 1). CXC chemokines classically were thought to be cytokines that are important in recruitment of leuko- involved in the chemotaxis of neutrophils. Many chemo- cytes and angiogenesis. They exert chemotactic activity kines may have arisen from reduplication of ancestral toward a variety of cell types (2–7). Some chemokines, genes (13). Hence, CXC chemokines that act on neutro- particularly CXC chemokines containing the ELR motif, phils are clustered on chromosome 4q12–13 (13). How- are angiogenic. The last few years have seen a rapid ever, some genes of more newly discovered CXC che- development of studies aimed at targeting proinflamma- mokines that recruit lymphocytes tend to be located tory chemokines or their receptors in RA and animal away from the major clusters (13).
    [Show full text]
  • Human XCL2 Protein (His Tag)
    Human XCL2 Protein (His Tag) Catalog Number: 13502-H08B General Information SDS-PAGE: Gene Name Synonym: SCM-1b; SCM1B; SCYC2 Protein Construction: A DNA sequence encoding the human XCL2 (Q9UBD3) (Met 1-Gly 114) was fused with a polyhistidine tag at the C-terminus. Source: Human Expression Host: Baculovirus-Insect Cells QC Testing Purity: > 90 % as determined by SDS-PAGE Endotoxin: Protein Description < 1.0 EU per μg of the protein as determined by the LAL method XCL2 is a small cytokine belonging to the XC chemokine family. Stability: Chemokines are a group of cytokines. Members of this group of so-called C-Chemokines belong to the SCY family of cytokines and are designated Samples are stable for up to twelve months from date of receipt at -70 ℃ XCL (L for ligand) followed by a number. XCL2 is the new designation of SCM-1-beta. XCL2 is highly related to another chemokine called XCL1. Predicted N terminal: Val 22 XCL2 gene is located on chromosome 1 in humans. XCL2 is predominantly Molecular Mass: expressed in activated T cells, but can also be found at low levels in unstimulated cells. XCL2 induces chemotaxis of cells expressing the The secreted recombinant human XCL2 comprises 103 amino acids and chemokine receptor XCR1. XCL2 gene has been proposed to participate in has a predicted molecular mass of 11.7 kDa. The apparent molecular pathways (Chemokine signaling pathway, Cytokine-cytokine receptor mass of rh XCL2 is approximately 18-20 kDa in SDS-PAGE under interaction) and processes (blood circulation, signal transduction, reducing conditions. chemotaxis, immune response).
    [Show full text]
  • Review Chemokines and Their Receptors in Disease
    Histol Histopathol (2005) 20: 907-926 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review Chemokines and their receptors in disease L. Bendall Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, Australia Summary. Chemokines are a family of structurally has 3 amino acids separating the 2 cysteines. related low molecular weight (8–10 kDa) proteins that Chemokines can also be classified according to their are important for the organization of tissues during primary function. Most chemokines are primarily development and regulate cell motility and localization involved in inflammatory responses (inflammatory both during development and in the adult. In the adult, chemokines), others are principally involved in this function is predominately related to the trafficking homeostatic functions (homeostatic chemokines) while of leukocytes, although more recently the impact of others perform functions related to both processed (dual these molecules on other cell types has become apparent. function chemokines). In addition to acting as agonists, Chemokines mediate their effects by binding seven amino terminal truncation of many chemokines results in transmembrane, G-protein coupled, receptors. In their inactivation and in some instances, including CCL2 addition to their primary role in regulating cell motility, (9-67) and CCL7 (5-76), results in antagonistic activity they can also influence cell survival and proliferation. (McQuibban et al., 2000, 2002), suggesting that Antagonists for a number of chemokine receptor have proteolytic cleavage of chemokines may act to terminate been developed, raising the possibility of interfering an inflammatory response. with chemokine function as a therapeutic tool. This Chemokine receptors are members of a class of review focuses on the emerging roles for chemokines in seven-transmembrane G protein-coupled receptors normal physiology and disease.
    [Show full text]
  • Microarray Analysis of Colorectal Cancer Stromal Tissue Reveals Upregulation of Two Oncogenic Mirna Clusters
    Published OnlineFirst March 27, 2012; DOI: 10.1158/1078-0432.CCR-11-1078 Clinical Cancer Human Cancer Biology Research Microarray Analysis of Colorectal Cancer Stromal Tissue Reveals Upregulation of Two Oncogenic miRNA Clusters Naohiro Nishida1,4, Makoto Nagahara2, Tetsuya Sato3, Koshi Mimori1, Tomoya Sudo1, Fumiaki Tanaka1, Kohei Shibata1, Hideshi Ishii1,4, Kenichi Sugihara2, Yuichiro Doki4, and Masaki Mori1,4 Abstract Purpose: Cancer stroma plays an important role in the progression of cancer. Although alterations in miRNA expression have been explored in various kinds of cancers, the expression of miRNAs in cancer stroma has not been explored in detail. Experimental Design: Using a laser microdissection technique, we collected RNA samples specific for epithelium or stroma from 13 colorectal cancer tissues and four normal tissues, and miRNA microarray and gene expression microarray were carried out. The expression status of miRNAs was confirmed by reverse transcriptase PCR. Furthermore, we investigated whether miRNA expression status in stromal tissue could influence the clinicopathologic factors. Results: Oncogenic miRNAs, including two miRNA clusters, miR-17-92a and miR-106b-25 cluster, were upregulated in cancer stromal tissues compared with normal stroma. Gene expression profiles from cDNA microarray analyses of the same stromal tissue samples revealed that putative targets of these miRNA clusters, predicted by Target Scan, such as TGFBR2, SMAD2, and BMP family genes, were significantly downregulated in cancer stromal tissue. Downregulated putative targets were also found to be involved in cytokine interaction and cellular adhesion. Importantly, expression of miR-25 and miR-92a in stromal tissues was associated with a variety of clinicopathologic factors. Conclusions: Oncogenic miRNAs were highly expressed in cancer stroma.
    [Show full text]
  • Chemokine and Chemokine Receptor Profiles in Metastatic Salivary Adenoid Cystic Carcinoma ASHLEY C
    ANTICANCER RESEARCH 36 : 4013-4018 (2016) Chemokine and Chemokine Receptor Profiles in Metastatic Salivary Adenoid Cystic Carcinoma ASHLEY C. MAYS, XIN FENG, JAMES D. BROWNE and CHRISTOPHER A. SULLIVAN Department of Otolaryngology, Wake Forest School of Medicine, Winston Salem, NC, U.S.A. Abstract. Aim: To characterize the chemokine pattern in distant metastasis (2-5). According to Ko et al. , 75% of metastatic salivary adenoid cystic carcinoma (SACC). patients with initial nodal involvement eventually developed Materials and Methods: Real-time polymerase chain distant metastasis. Patients with lung metastasis have a poor reaction (RT-PCR) was used to compare chemokine and prognosis (6). chemokine receptor gene expression in two SACC cell lines: The development of distant metastatic disease is the chief SACC-83 and SACC-LM (lung metastasis). Chemokines and cause for mortality (7, 8). Primary treatment is complete receptor genes were then screened and their expression surgical resection when feasible with adjuvant radiotherapy. pattern characterized in human tissue samples of non- The role of chemotherapy is debatable. Treatment of recurrent SACC and recurrent SACC with perineural metastatic ACC has been difficult to date due to lack of invasion. Results: Expression of chemokine receptors specific targets for metastatic cells (1). Though the steps that C5AR1, CCR1, CCR3, CCR6, CCR7, CCR9, CCR10, must occur in the metastatic event are well characterized, it CXCR4, CXCR6, CXCR7, CCRL1 and CCRL2 were higher remains unclear why or how ACC cells ultimately “choose” in SACC-83 compared to SACC-LM. CCRL1, CCBP2, or are ”chosen” to migrate to a specific metastatic site. A CMKLR1, XCR1 and CXCR2 and 6 chemokine genes mounting body of evidence suggests that cytokine-like (CCL13, CCL27, CXCL14, CMTM1, CMTM2, CKLF) were molecules called chemokines play a significant role in more highly expressed in tissues of patients without tumor directing the cellular traffic in metastatic melanoma, lung, recurrence/perineural invasion compared to those with breast and ACC cancers (9-15).
    [Show full text]
  • Open Mithun Shah.Pdf
    The Pennsylvania State University The Graduate School Department of Molecular Medicine ROLE OF SPHINGOLIPID SIGNALING IN PATHOGENESIS OF LARGE GRANULAR LYMPHOCYTE LEUKEMIA A Dissertation in Molecular Medicine by Mithun Vinod Shah © 2009 Mithun Vinod Shah Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2009 ii The dissertation of Mithun Vinod Shah was reviewed and approved* by the following: Thomas P. Loughran, Jr. Professor of Medicine Dissertation Advisor Co-Chair of Committee Rosalyn B. Irby Assistant Professor of Medicine Co-chair of Committee Gary Clawson Professor of Pathology, and Biochemistry and Molecular Biology Edward J. Gunther Assistant Professor of Medicine Charles H. Lang Director, Molecular Medicine Graduate Program *Signatures are on file in the Graduate School iii ABSTRACT Large granular lymphocyte (LGL) leukemia is a disorder of mature cytotoxic cells. LGL leukemia is characterized by accumulation of cytotoxic cells in blood and infiltration in bone marrow and other tissues. Leukemic LGL could arise from expansion of either CD3+ CD8+ T-cells (T-cell LGL leukemia or T-LGL leukemia) or those arising from CD3- natural killer (NK)-cells (NK-cell LGL leukemia or NK-LGL leukemia). LGL leukemia is a rare disorder consisting of less than 5% of non-B cell leukemia. Clinically, LGL leukemia can manifest along a spectrum of disorders ranging from slowly progressing indolent disorder to an aggressive leukemia that could be fatal within months. About fifty percent of LGL leukemia patients also present with variety of autoimmune conditions, rheumatoid arthritis being the most common one. Normally, following antigen clearance, cytotoxic T-lymphocytes (CTL) become sensitive to Fas-mediated apoptosis resulting in activation-induced cell death (AICD).
    [Show full text]