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Post-translational control of chemokines: A role for decoy receptors?

Cancer Research UK Beatson Laboratories, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Immunology Letters (Impact Factor: 2.37). 02/2005; 96(2):163-74. DOI: 10.1016/j.imlet.2004.08.018
Source: PubMed

ABSTRACT It is well-established that chemokines play a critical role in the orchestration of inflammation and immunity. Interactions between chemokines and their receptors are essential for the homing of specific subsets of leukocytes to their functional microenvironments. They also influence other diverse biological processes such as development, leukocyte activation, Th1/Th2 polarisation, tumour metastasis, angiogenesis, and HIV pathogenesis. However, despite their importance, only now are we beginning to understand the complex regulation brought to bear on these molecules. In this review, we discuss a number of these key chemokine regulators that exert their influence once these proteins have been synthesised. We examine (i) chemokine storage, release, and presentation, (ii) protease regulation, (iii) viral manipulation of host chemokines, and (iv) natural mammalian receptor antagonists. Principally, the growing evidence for a role for decoy receptors in the chemokine system is discussed. In particular, the potential decoy function of the 'silent' pro-inflammatory chemokine receptor D6 is described alongside two other candidate decoy receptor molecules, DARC, and CCX-CKR. Dissecting the biological and pathological function of these chemokine controllers will lead to a deeper understanding of chemokine regulation, and may reveal novel strategies to therapeutically modify the chemokine system.

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    • "In each case, these strategies are specific for the blockade of single ligands or receptors. Given the multiple redundancy within both chemokines and their receptors, it seems likely that a strategy to simultaneously modulate a number of chemokines will have a clinical advantage (11); indeed, naturally occurring chemokine “scavenger” receptors such as D6 and DARC can perform this function in vivo by clearance of groups of chemokines (12). Notably, GPCR agonists, including the chemokines, can induce both homologous and heterologous receptor tolerance, suggesting that single agents might negate the potential of a cell to respond to multiple chemokines (5). "
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    The FASEB Journal 09/2009; 23(11):3906-16. DOI:10.1096/fj.09-134643 · 5.48 Impact Factor
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    • "Several papers have focused recently on “scavenger receptors” which are “atypical” receptors playing a role in scavenging or altering the localization of chemoattractant molecules such as chemokines and complement molecules [8, 10, 25]. The “atypical” receptor family comprised the receptors D6, the Duffy Antigen/Receptor for Chemokines and CCRL1/CCX-CKR [8, 10]. CCRL1 was described in mice and humans but there was no data about this receptor in the pig [9, 16, 34, 37]. "
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    • ", 1999 ) und können somit keine Signalkomplexe bilden . ( Comerford and Nibbs , 2005 ) . Bis zum heutigen Tag sind vier Decoyrezeptoren charakterisiert worden : TRAIL - R3 ( DcR - 1 , LIT , TRID ) ( Mongkolsapaya et al . "
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    ABSTRACT: Hirntumore, wie das Glioblastom multiform (GBM), zählen zu den häufigsten und bösartigsten Tumoren des zentralen Nervensystems (ZNS). Trotz sich weiterentwickelnder Diagnosemöglichkeiten ist die Überlebensrate sehr gering. Weniger als 3% der Patienten überleben die ersten 5 Jahre nach der Diagnose. Der klinische Verlauf bösartiger Glioblastome ist von der Invasion isolierter Tumorzellen in das normale Gehirngewebe abhängig. Diese Zellen entkommen der operativen Entfernung des Tumors. Sie sind Ziel der postoperativen Strahlen- und Chemotherapie. Diese postoperativen Therapieformen induzieren Apoptose durch Induktion der Expression der Todesrezeptoren und ihrer Liganden, wie beispielsweise das CD95-(Fas/Apo-1) Todessystem. In den letzten 20 Jahren wurden immer wieder neue Therapieformen entwickelt, die oftmals aber einen gegenteiligen Effekt erzielten. So führten beispielsweise die Antiangiogenese Medikamente zu einem verstärkten Auswachsen der Zellen aus dem Glioblastom (Lamszus et al., 2003). Ein weiteres Problem ist die zunehmende Resistenz der Glioblastome gegenüber apoptoseinduzierender Therapien. Das Anliegen dieser Studie war den Mechanismus der Invasion genauer zu untersuchen. Wir konnten zeigen, dass die Stimulierung des CD95-Rezeptors einen Anstieg der Migration/Invasion in apoptoseresistenten etablierten und primären Glioblastomzellen auslöste. Diese Zunahme konnte sowohl mit exogenen Stimuli (α-Apo-1 Antikörper bzw. LZ-CD95L) als auch durch die Hochregulierung des endogenen CD95/CD95L-Systems nach -Bestrahlung beobachtet werden. Der CD95-vermittelte Anstieg konnte durch einen neutralisierenden Antikörper gegen CD95L blockiert werden. Die Tendenz der Zellen zu migrieren, anstatt durch Apoptose zu sterben, steigt mit dem Malignitätsgrad primärer Glioblastome an. Der Signalweg der CD95-vermittelten Migration läuft über die Aktivierung der PI3Kinase (PI3K), der Integrin-Linked-Kinase (ILK), der Inhibierung von GSK3 und der Expression der Matrix-Metalloproteinasen (MMPs). Caspasen sind an diesem Signalweg nicht beteiligt. Das direkte Verbindungsglied unterhalb des CD95-Rezeptors konnte in dieser Studie nicht detektiert werden. Das „phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15-kDalton“ (PED/PEA-15) wurde als möglicher Kandidat untersucht. Jedoch konnte nach dem Ausschalten der PED/PEA-15-Expression keine Veränderung in der Inhibierung von GSK3 detektiert werden. Vor diesem Hintergrund sollten die postoperativen Therapieformen sehr gut überlegt und durch vorherige Test des entnommen Tumors auf seine Reaktion gegenüber CD95-Stimulierung getroffen werden. Gliomas account for more than 50% of all brain tumors and are by far the most common primary brain tumors in adults. Despite, development of new diagnostic technologies, the survivalrate is extremely low. Only 3% are still alive five years after diagnosis. The clinical outcome of malignant gliomas depends on the invasion of isolated tumor cells in the nomal brain tissue. Migrating cells can escape the surgical ablation of the tumor and are then the prime targets of post-surgical radiotherapy and adjuvant chemotherapy. Chemotherapeutic agents and irradiation act primarily by inducing apoptosis. This induction of apoptosis often involves activation of the CD95 (Apo-1/Fas) death receptor/ligand system. Nevertheless, most malignant glioma cells are resistant to CD95-induced apoptosis. Here we show that triggering of CD95 increases migration/invasion in apoptosis-resistant human long-term and primary glioma cultures. The tendency of primary glioma tumors of migration over apoptosis increases with the degree of malignancy. CD95 mediates migration via the PI3K/ILK/GSK3/MMP pathway in a caspase-independent manner. Futhermore we tried to figure out the linker molecule downstream of CD95. A possible candidate was Phosphoprotein enriched in Diabetes/Phosphoprotein enriched in Astrocytes-15-kDalton“ (PED/PEA-15). Knockdown experiments excluded PED/PEA-15 as linker molecule in the signalingpathway of migration mediated through CD95/CD95L-System. Most importantly, -irradiation also increased migration of cells resistant to CD95-induced death. Irradiation-mediated migration could be blocked by neutralization of CD95L. Thus, a tumor‘s reaction to CD95 stimulation should dictate subsequent therapy options.
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