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Timothy N C Wells - One of the best experts on this subject based on the ideXlab platform.
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hiv 1 tat protein mimicry of Chemokines
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Adriana Albini, Amanda E. I. Proudfoot, Timothy N C Wells, Silvano Ferrini, Roberto Benelli, Sabrina Sforzini, Daniela Giunciuglio, M G Aluigi, Sami Alouani, Giuliano MarianiAbstract:The HIV-1 Tat protein is a potent chemoattractant for monocytes. We observed that Tat shows conserved amino acids corresponding to critical sequences of the Chemokines, a family of molecules known for their potent ability to attract monocytes. Synthetic Tat and a peptide (CysL24–51) encompassing the “chemokine-like” region of Tat induced a rapid and transient Ca2+ influx in monocytes and macrophages, analogous to β-Chemokines. Both monocyte migration and Ca2+ mobilization were pertussis toxin sensitive and cholera toxin insensitive. Cross-desensitization studies indicated that Tat shares receptors with MCP-1, MCP-3, and eotaxin. Tat was able to displace binding of β-Chemokines from the β-chemokine receptors CCR2 and CCR3, but not CCR1, CCR4, and CCR5. Direct receptor binding experiments with the CysL24–51 peptide confirmed binding to cells transfected with CCR2 and CCR3. HIV-1 Tat appears to mimic β-chemokine features, which may serve to locally recruit chemokine receptor-expressing monocytes/macrophages toward HIV producing cells and facilitate activation and infection.
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glycosaminoglycans mediate cell surface oligomerization of Chemokines
Biochemistry, 1997Co-Authors: Arlene J Hoogewerf, Amanda E. I. Proudfoot, Gabriele S V Kuschert, Frederic Borlat, Ian Clarklewis, Christine A Power, Timothy N C WellsAbstract:Chemokines are 8−10 kDa proteins involved in the control of leukocyte trafficking and activation. In free solution, Chemokines are monomers at physiologic concentrations, although many multimerize at higher concentrations. Cell surface heparan sulfate may sequester Chemokines, increasing their local concentrations and facilitating their binding to receptors expressed on leukocytes. In competitive binding assays using immobilized heparin, a 2−3-fold increase in the bound radiolabeled chemokine was seen with increasing concentrations of unlabeled chemokine in the nanomolar range. Unlabeled chemokine concentrations between 0.25 and 50 μM were needed to compete the bound radioactivity. This biphasic competition curve was not seen for N-methyl-L25 IL-8, a variant of IL-8 which is unable to dimerize. In addition, complexes of chemokine and heparin eluted from gel filtration columns with apparent molecular masses of 33−60 kDa, suggesting that chemokine multimerization had occurred. The physiological relevance of...
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glycosaminoglycans mediate cell surface oligomerization of Chemokines
Biochemistry, 1997Co-Authors: Arlene J Hoogewerf, Amanda E. I. Proudfoot, Gabriele S V Kuschert, Frederic Borlat, Ian Clarklewis, Christine A Power, Timothy N C WellsAbstract:Chemokines are 8-10 kDa proteins involved in the control of leukocyte trafficking and activation. In free solution, Chemokines are monomers at physiologic concentrations, although many multimerize at higher concentrations. Cell surface heparan sulfate may sequester Chemokines, increasing their local concentrations and facilitating their binding to receptors expressed on leukocytes. In competitive binding assays using immobilized heparin, a 2-3-fold increase in the bound radiolabeled chemokine was seen with increasing concentrations of unlabeled chemokine in the nanomolar range. Unlabeled chemokine concentrations between 0.25 and 50 microM were needed to compete the bound radioactivity. This biphasic competition curve was not seen for N-methyl-L25 IL-8, a variant of IL-8 which is unable to dimerize. In addition, complexes of chemokine and heparin eluted from gel filtration columns with apparent molecular masses of 33-60 kDa, suggesting that chemokine multimerization had occurred. The physiological relevance of this multimerization process was seen from studies using human endothelial cells. The endothelial cell binding sites for IL-8, RANTES, and MCP-1 were deduced to be glycosaminoglycans since competition assays showed the biphasic curves and micromolar IC50 values seen in studies with immobilized heparin, and mRNA for known chemokine receptors was not detected. Furthermore, digestion of endothelial cell monolayers with glycosaminidases decreased chemokine binding by up to 80%. Glycosaminoglycans can act as modulators of the ligand binding affinity of chemokine receptor-bearing cells. Removal of glycosaminoglycans from CHO cells expressing chemokine receptors CXCR1, CCR1, or CCR2 resulted in 40-70% decreases in the binding of RANTES, MCP-1, IL-8, and MIP-1alpha. Our data show that cell surface glycosaminoglycans induce polymerization of Chemokines, increasing their local concentration and therefore enhancing their effects on high-affinity receptors within the local microenvironment.
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effect of a cc chemokine receptor antagonist on collagen induced arthritis in dba 1 mice
Immunology Letters, 1997Co-Authors: Platerzyberk Christine, Amanda E. I. Proudfoot, Arlene J Hoogewerf, Christine A Power, Timothy N C WellsAbstract:Chemokines are small proteins that selectively activate and recruit leukocytes to sites of inflammation. Several of them, including the CC Chemokines RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and the CXC Chemokines IL-8, GRO-alpha, ENA-78 have been identified in rheumatoid synovium, implicating a potential role for these molecules in rheumatoid arthritis. We have investigated the expression patterns of CC chemokine receptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration of MetRANTES, a modified chemokine which is a nanomolar antagonist of certain CC chemokine receptors. The mRNA expression pattern of the Chemokines and their receptors in the joints of arthritic mice was investigated using reverse transcriptase-PCR and in situ hybridization. An upregulation of the CC chemokine receptors mCCR1, mCCR2; mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control animals. In addition, injections of MetRANTES reduced the incidence of disease in a dose dependent manner. Furthermore, in MetRANTES-treated mice that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstrate a role for CC Chemokines and their receptors in inflammatory joint destruction and support the use of chemokine receptor antagonists as potential tools to control inflammatory diseases such as rheumatoid arthritis.
Reinhold Forster - One of the best experts on this subject based on the ideXlab platform.
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chemokine receptors version 2020 5 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2020Co-Authors: Francoise Bachelerie, Joshua M Farber, Reinhold Forster, Gerard J Graham, Adit Benbaruch, Amanda M Burkhardt, Christophe Combadiere, Israel F Charo, Rebecca Hills, Richard HorukAbstract:Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [431, 430, 32]) comprise a large subfamily of 7TM proteins that bind one or more Chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many Chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-Chemokines; n= 28), CXC (also known as α-Chemokines; n= 17) and CX3C (n= 1) Chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C Chemokines (n= 2) have only the second and fourth cysteines found in other Chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most Chemokines bind to more than one receptor subtype. Receptors for inflammatory Chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of Chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [33]. There can be substantial cross-species differences in the sequences of both Chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [684] and aliases.
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chemokine receptors version 2019 5 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Francoise Bachelerie, Joshua M Farber, Reinhold Forster, Gerard J Graham, Adit Benbaruch, Richard Horuk, Christophe Combadiere, Israel F Charo, Rebecca Hills, Massimo LocatiAbstract:Chemokine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [426, 425, 32]) comprise a large subfamily of 7TM proteins that bind one or more Chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many Chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [32].Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-Chemokines; n= 28), CXC (also known as α-Chemokines; n= 17) and CX3C (n= 1) Chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C Chemokines (n= 2) have only the second and fourth cysteines found in other Chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most Chemokines bind to more than one receptor subtype. Receptors for inflammatory Chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of Chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [33]. There can be substantial cross-species differences in the sequences of both Chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [675] and aliases.
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active shaping of chemokine gradients by atypical chemokine receptors a 4d live cell imaging migration assay
Methods in Enzymology, 2016Co-Authors: Kathrin Werth, Reinhold ForsterAbstract:Diffusion of Chemokines away from their site of production results in the passive formation of chemokine gradients. We have recently shown that chemokine gradients can also be formed in an active manner, namely by atypical chemokine receptors (ACKRs) that scavenge Chemokines locally. Here, we describe an advanced method that allows the visualization of leukocyte migration in a three-dimensional environment along a chemokine gradient that is actively established by cells expressing an ACKR. Initially developed to visualize the migration of dendritic cells along gradients of CCL19 or CCL21 that were actively shaped by an ACKR4-expressing cell line, we expect that this chamber system can be exploited to study many other combinations of atypical and conventional chemokine receptor-expressing cells.
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distinct patterns and kinetics of chemokine production regulate dendritic cell function
European Journal of Immunology, 1999Co-Authors: Federica Sallusto, Belinda Palermo, Minja Miettinen, Ralf Burgstahler, Danielle Lenig, Sampsa Matikainen, Reinhold Forster, Ilkka Julkunen, Antonio LanzavecchiaAbstract:Dendritic cells (DC) have been showed to both produce and respond to Chemokines. To understand how this may impact on DC function, we analyzed the kinetics of chemokine production and responsiveness during DC maturation. After stimulation with LPS, TNF-α or CD40 ligand, the inflammatory Chemokines MIP-1α, MIP-1β and IL-8 were produced rapidly and at high levels, but only for a few hours, while RANTES and MCP-1 were produced in a sustained fashion. The constitutive Chemokines TARC, MDC and PARC were expressed in immature DC and were up-regulated following maturation, while ELC was produced only at late time points. Activated macrophages produced a similar spectrum of Chemokines, but did not produce TARC and ELC. In maturing DC chemokine production had different impact on chemokine receptor function. While CCR1 and CCR5 were down-regulated by endogenous or exogenous Chemokines, CCR7 levels gradually increased in maturing DC and showed a striking resistance to ligand-induced down-regulation, explaining how DC can sustain the response to SLC and ELC throughout the maturation process. The time-ordered production of inflammatory and constitutive Chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other cells for the afferent and efferent limb of the immune response.
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distinct patterns and kinetics of chemokine production regulate dendritic cell function
European Journal of Immunology, 1999Co-Authors: Federica Sallusto, Belinda Palermo, Minja Miettinen, Ralf Burgstahler, Danielle Lenig, Sampsa Matikainen, Reinhold Forster, Ilkka Julkunen, Antonio LanzavecchiaAbstract:Dendritic cells (DC) have been showed to both produce and respond to Chemokines. To understand how this may impact on DC function, we analyzed the kinetics of chemokine production and responsiveness during DC maturation. After stimulation with LPS, TNF-alpha or CD40 ligand, the inflammatory Chemokines MIP-1alpha, MIP-1beta and IL-8 were produced rapidly and at high levels, but only for a few hours, while RANTES and MCP-1 were produced in a sustained fashion. The constitutive Chemokines TARC, MDC and PARC were expressed in immature DC and were up-regulated following maturation, while ELC was produced only at late time points. Activated macrophages produced a similar spectrum of Chemokines, but did not produce TARC and ELC. In maturing DC chemokine production had different impact on chemokine receptor function. While CCR1 and CCR5 were down-regulated by endogenous or exogenous Chemokines, CCR7 levels gradually increased in maturing DC and showed a striking resistance to ligand-induced down-regulation, explaining how DC can sustain the response to SLC and ELC throughout the maturation process. The time-ordered production of inflammatory and constitutive Chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other cells for the afferent and efferent limb of the immune response.
Antonio Lanzavecchia - One of the best experts on this subject based on the ideXlab platform.
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distinct patterns and kinetics of chemokine production regulate dendritic cell function
European Journal of Immunology, 1999Co-Authors: Federica Sallusto, Belinda Palermo, Minja Miettinen, Ralf Burgstahler, Danielle Lenig, Sampsa Matikainen, Reinhold Forster, Ilkka Julkunen, Antonio LanzavecchiaAbstract:Dendritic cells (DC) have been showed to both produce and respond to Chemokines. To understand how this may impact on DC function, we analyzed the kinetics of chemokine production and responsiveness during DC maturation. After stimulation with LPS, TNF-α or CD40 ligand, the inflammatory Chemokines MIP-1α, MIP-1β and IL-8 were produced rapidly and at high levels, but only for a few hours, while RANTES and MCP-1 were produced in a sustained fashion. The constitutive Chemokines TARC, MDC and PARC were expressed in immature DC and were up-regulated following maturation, while ELC was produced only at late time points. Activated macrophages produced a similar spectrum of Chemokines, but did not produce TARC and ELC. In maturing DC chemokine production had different impact on chemokine receptor function. While CCR1 and CCR5 were down-regulated by endogenous or exogenous Chemokines, CCR7 levels gradually increased in maturing DC and showed a striking resistance to ligand-induced down-regulation, explaining how DC can sustain the response to SLC and ELC throughout the maturation process. The time-ordered production of inflammatory and constitutive Chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other cells for the afferent and efferent limb of the immune response.
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distinct patterns and kinetics of chemokine production regulate dendritic cell function
European Journal of Immunology, 1999Co-Authors: Federica Sallusto, Belinda Palermo, Minja Miettinen, Ralf Burgstahler, Danielle Lenig, Sampsa Matikainen, Reinhold Forster, Ilkka Julkunen, Antonio LanzavecchiaAbstract:Dendritic cells (DC) have been showed to both produce and respond to Chemokines. To understand how this may impact on DC function, we analyzed the kinetics of chemokine production and responsiveness during DC maturation. After stimulation with LPS, TNF-alpha or CD40 ligand, the inflammatory Chemokines MIP-1alpha, MIP-1beta and IL-8 were produced rapidly and at high levels, but only for a few hours, while RANTES and MCP-1 were produced in a sustained fashion. The constitutive Chemokines TARC, MDC and PARC were expressed in immature DC and were up-regulated following maturation, while ELC was produced only at late time points. Activated macrophages produced a similar spectrum of Chemokines, but did not produce TARC and ELC. In maturing DC chemokine production had different impact on chemokine receptor function. While CCR1 and CCR5 were down-regulated by endogenous or exogenous Chemokines, CCR7 levels gradually increased in maturing DC and showed a striking resistance to ligand-induced down-regulation, explaining how DC can sustain the response to SLC and ELC throughout the maturation process. The time-ordered production of inflammatory and constitutive Chemokines provides DC with the capacity to self-regulate their migratory behavior as well as to recruit other cells for the afferent and efferent limb of the immune response.
Stephan Segerer - One of the best experts on this subject based on the ideXlab platform.
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Chemokines in Renal Diseases
2020Co-Authors: Stephan Segerer, Peter J NelsonAbstract:The Chemokines, members of a large family of chemotactic cytokines, act as directional cues for sorting inflammatory cell subsets to sites of inflammation or lymphoid microenvironments. In addition to their effects on migration, Chemokines can also activate effector function in leukocytes and are involved in cell proliferation and angiogenesis. Therefore, it is not surprising that Chemokines play important roles in a wide range of human diseases, including genetic immunodeficiencies, infections, autoimmune diseases, and malignant tumors. INTRODUCTION Inflammatory cells play pivotal roles in renal injury and renal allograft rejection Chemokines are small, chemotactic cytokines that provide a complex signal system for cell communication between all kinds of cells, including leukocytes The literature on Chemokines in kidney diseases currently focuses on (1) Chemokines as therapeutic targets, (2) urinary Chemokines and chemokine receptors as diagnostic tools, (3) chemokine polymorphisms as predisposing or prognostic factors, and (4) characterization of Chemokines and chemokine receptors in human kidney diseases and allograft rejection. In this review, we will start with the basics and follow with these topics primarily focusing on what has been published on the various renal diseases since mid 2003 (for detailed reviews of earlier data see SOME BASIC "CHEMOKINENOLOGY" The human chemokine family consists of over 40 ligands (L) and 19 corresponding receptors (R) Two functionally characterized groups, i.e., inflammatory and homeostatic Chemokines, have been described. Inflammatory Chemokines like CCL2/MCP-1, CCL5/RANTES, or CXCL10/IP-10 are rapidly upregulated and released by proinflammatory cytokines. Homeostatic Chemokines, on the other hand, are involved in tissue homeostasis and cellular recirculation under noninflammatory conditions. The renal literature has focused on inflammatory Chemokines, with very little exceptions [24,25,26]. Chemokine receptors are seven, transmembrane-spanning proteins coupled to heterotrimeric G proteins and activate various intracellular pathways like small GTPases and kinases 836 Segerer and Nelson: Chemokines in Renal Diseases TheScientificWorldJOURNAL (2005) 5, 835-844 A series of seven, transmembrane, chemokine-binding proteins that do not signal in response to binding and are now referred to as interceptors (chemokine-internalizing receptors) are under study [27]. Two members of this family are DARC (the duffy antigen receptor) and D6. DARC binds both CC as well as CXC Chemokines Chemokines AS THERAPEUTIC TARGETS All intrinsic renal cells can express Chemokines in response to stress (for details see The MRL(lpr/lpr) mouse is a well-defined model of lupus nephritis [33]. A variety of Chemokines are upregulated during the disease course (including CCL2/MCP-1 and CCL5/RANTES), associated with the recruitment of inflammatory cells, both to the glomerular tuft and the tubulointerstitium [34]. CCL2/MCP-1-deficient mice demonstrated a significant improvement of the disease course [35]. Deficiency of the corresponding receptor CCR2 resulted in a reduction in the inflammatory cell recruitment (both T cells and macrophages) and improved renal morphology (Perez de , Unpublished data, J. Am. Soc. Nephrol. 15, 686 A). Gene transfer of an NH2-terminal deletion mutant of the MCP-1 gene (7ND) was used to interfere with CCR2 signaling [36,37]. This approach was shown to reduce renal inflammation and prolonged survival [36]. Treatment with the CCR1 antagonist BX471 was found to reduce blood urea nitrogen levels, interstitial T cell and macrophage accumulation, and decreased interstitial fibrosis in this model [33]. An additional approach designed to interfere with chemokine signaling involved the transfection of an N-terminally truncated CX3CL1/fractalkine gene (Fkn-AT) into a fibroblastoid cell line, which was then injected subcutaneously [38]. MRL/lpr mice treated with Fkn-AT before the onset or during the early stages of lupus nephritis demonstrated a reduction of glomerular hypercellularity, glomerulosclerosis, crescent formation, and vasculitis [38]. While these results demonstrate a beneficial effect of chemokine blockade in the MRL-lpr mouse using various approaches, more needs to be learned about the specific chemokine receptor expression by inflammatory cells infiltrating the glomeruli during human lupus nephritis. The role of macrophage-derived chemokine (CCL22/MDC) and its corresponding receptor (CCR4) has been studied in a nephrotoxic nephritis model in rats [39]. Induction of CCL22/MDC mRNA and protein was detected in nephritic glomeruli. A blockade of CCL22/MDC using specific antibody did not affect the early phase of the disease, but did suppress macrophage recruitment, crescent formation, and deterioration of renal function in the later phase of the disease [39]. Adriamycin nephropathy is a toxic model induced in mice or rats that leads to proteinuria and interstitial fibrosis [40,41]. During the disease course, an increase in expression of Chemokines such as CCL5/RANTES and CCL2/MCP-1, and their corresponding receptors, is seen. The induction of autoantibodies directed against CCL5/RANTES and CCL2/MCP-1, achieved through vaccination with naked DNA in rats, resulted in decreased proteinuria, improved creatinine-clearance, conservation of renal morphology, and reduced inflammatory interstitial infiltrates [40]. Accordingly, blocking CCR1 (a receptor for CCL5/RANTES) with a small molecule antagonist decreased interstitial T cell and macrophage accumulation, and reduced interstitial fibroblast accumulation and interstitial fibrosis [41]. To study the role of hepatocyte growth factor (HGF) in renal inflammation, rats with subtotal nephrectomy were treated with recombinant HGF or with a blocking antibody against HGF [42]. HGF treatment reduced tubular CCL2/MCP-1 and CCL5/RANTES expression and decreased inflammatory cell recruitment. Blocking endogenous HGF had the opposite effect [42]. Therefore, the beneficial effects of 837 Segerer and Nelson: Chemokines in Renal Diseases TheScientificWorldJOURNAL (2005) 5, 835-844 HGF in progressive renal injury may be mediated, in part, through reduction of selective chemokine expression. Unilateral ureter obstruction is commonly used as a rapid model of interstitial fibrosis in mice Collagen 4A3-deficient mice develop progressive renal failure, mimicking human Alports syndrome Ischemia/reperfusion (I/R) injury promotes delayed graft function and is a major obstacle to longterm renal allograft survival. In a rat I/R model (4-h cold ischemia), the induction of CINC (a rat homolog of CXCL8/IL-8) was associated with granulocyte recruitment As with any effective agent, chemokine antagonists may have adverse effects related to specific function of the chemokine in other systems, to unspecific interactions, or organ toxicity. Met-RANTES and AOP-RANTES, two CCL5/RANTES-based functional antagonists, have been found to aggravate glomerular damage and proteinuria in mice with immune complex glomerulonephritis, despite a reduction of glomerular leukocyte infiltration CHARACTERIZATION OF Chemokines AND CHEMOKINE RECEPTORS IN HUMAN KIDNEY DISEASES AND ALLOGRAFT REJECTION It is now generally accepted that the severity of interstitial injury correlates well with renal function and is of prognostic value for glomerular diseases Panzer et al. demonstrated a significant increase of CXCR3-positive cells during acute allograft rejection and a significant induction of the corresponding ligands URINARY Chemokines AND CHEMOKINE RECEPTORS AS DIAGNOSTIC TOOLS CCL2/MCP-1 mRNA and protein measured in the urine of patients with lupus nephritis correlated with the clinical disease activity and the histological activity score As described earlier, CXCR3 and its corresponding ligands are upregulated in patients with cellular renal allograft rejection. Therefore, measuring the corresponding ligands might represent a potential tool for the surveillance of allograft damage. In a baboon model of renal allograft rejection, the urinary excretion of CXCL9/Mig and CXCL10/IP-10 was significantly increased during acute allograft rejection and was found to rise before an increase in serum creatinine was seen These results build on reports, dating back to the middle of the 90s, that demonstrate that the measurement of Chemokines in the urine may represent an important tool in clinical nephrology. The clinical application has not been reached and larger, prospective studies are clearly needed to demonstrate clinical applicability and the impact on disease courses. Segerer and Nelson: Chemokines in Renal Diseases TheScientificWorldJOURNAL (2005) 5, 835-844 839 CHEMOKINE POLYMORPHISMS AS PREDISPOSING OR PROGNOSTIC FACTORS Genetic variations including single nucleotide polymorphisms (SNPs) in Chemokines or chemokine receptors have been linked to diverse inflammatory diseases. It is thought that these variations may change the tissue response to injury or the release of Chemokines by infiltrating cells. Several polymorphisms of chemokine and chemokine receptor genes of the host are linked to the course of allograft dysfunction after renal transplantation The CCR5Delta32 mutation has also been associated with a better renal outcome in patients with IgA nephropathy No association was found with -2518(A/G) MCP-1 or an additional RANTES/CCL5 polymorphism at -403 (G/A) and the course of IgA nephropathy In a prospective study, Böger et al. included 225 Caucasian patients with type 2 diabetes mellitus on dialysis for less than 2 years TOLL-LIKE RECEPTORS, Chemokines, AND RENAL DISEASES Toll-like receptors (TLR) are a family of receptors that bind to pathogen-associated molecular patterns 840 Segerer and Nelson: Chemokines in Renal Diseases TheScientificWorldJOURNAL (2005) 5, 835-844 SUMMARY Promise of chemokine-based therapeutics in renal disease is beginning to show results. Blockades of select receptors appear to reduce the infiltration of specific leukocytes and thereby limit tissue damage. In human glomerular diseases and allograft rejection, both CCR5 and CXCR3 are currently the most promising targets with CCR5 antagonists demonstrating therapeutic activity in patients with HIV infection and other new drugs in the pipeline (e.g., TAC 220) ACKNOWLEDGMENT
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the duffy antigen receptor for Chemokines transports Chemokines and supports their promigratory activity
Nature Immunology, 2009Co-Authors: Monika Pruenster, Ann Richmond, Jim Middleton, Liesbeth Mudde, Paula Bombosi, Svetla Dimitrova, Marion Zsak, Gerard J Graham, Stephan SegererAbstract:The Duffy antigen receptor for Chemokines (DARC) belongs to a family of ‘silent’ heptahelical chemokine receptors that do not couple to G proteins and fail to transmit measurable intracellular signals. DARC binds most inflammatory Chemokines and is prominently expressed on venular endothelial cells, where its function has remained contentious. Here we show that DARC, like other silent receptors, internalized Chemokines but did not effectively scavenge them. Instead, DARC mediated chemokine transcytosis, which led to apical retention of intact Chemokines and more leukocyte migration across monolayers expressing DARC. Mice overexpressing DARC on blood vessel endothelium had enhanced chemokine-induced leukocyte extravasation and contact-hypersensitivity reactions. Thus, interactions of Chemokines with DARC support their activity on apposing leukocytes in vitro and in vivo.
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expression of Chemokines and chemokine receptors during human renal transplant rejection
American Journal of Kidney Diseases, 2001Co-Authors: Stephan Segerer, Detlef Schlondorff, Yan Cui, Frank Eitner, Tracy Goodpaster, Kelly L Hudkins, Matthias Mack, Jeanpierre Cartron, Yves Colin, Charles E. AlpersAbstract:Abstract Infiltration of renal allografts by leukocytes is a hallmark of acute transplant rejection. Chemokines attract leukocytes bearing specific chemokine receptors, and the specific leukocyte chemokine receptor phenotype is associated with types of immune responses, ie, T helper subtype 1 (Th1; CXC chemokine receptor 3 [CXCR3], CC chemokine receptor 5 [CCR5]) versus Th2 (CCR3, CCR4, CCR8). We studied the expression of the chemokine monocyte chemoattractant protein-1 and the chemokine receptors CCR2B and CXCR4 messenger RNA (mRNA) by in situ hybridization, as well as the chemokine receptors Duffy antigen receptor for Chemokines (DARC) and CCR5 protein by immunohistochemistry in renal biopsy specimens with acute cellular rejection (n = 12) and acute vascular rejection (n = 8), transplant nephrectomy specimens (n = 6), and normal areas of tumor nephrectomy specimens (n = 5). CC Chemokines and CC chemokine receptor mRNA expression were evaluated by ribonuclease protection assay in specimens from four transplant nephrectomies and one tumor nephrectomy. Upregulation of mRNAs for the Chemokines, interferon-inducible protein-10 (IP-10); regulated on activation normal T-cell expressed and secreted; macrophage inflammatory protein-1α (MIP-1α); MIP-1β; and lymphotactin, as well as the chemokine receptors, CCR2 and CCR5, were documented during allograft rejection. CCR1 mRNA was detectable in both allografts and controls, but CCR3 and CCR8 were absent. The number of CXCR4, CCR5, and CCR2B mRNAs expressing leukocytes and DARC-positive vessels increased during rejection episodes. CXCR4 mRNA was the most widely expressed. Leukocytes in diffuse interstitial infiltrates were mainly CCR5 positive, but in areas in which leukocytes formed nodular aggregates of infiltrating cells, the number of CCR5-positive cells was low. Instead, leukocytes in these nodular aggregates mainly expressed CXCR4. DARC was expressed on peritubular capillaries, where it was upregulated in areas of interstitial infiltration. Induction of Chemokines during renal allograft rejection is accompanied by infiltration of leukocytes bearing the respective chemokine receptors. The upregulation of the CXCR3 ligand IP-10, as well as CCR5 and its ligands, in the absence of CCR3 and CCR8 is indicative that renal allograft rejection is primarily the result of a Th1-type immune response.
Amanda E. I. Proudfoot - One of the best experts on this subject based on the ideXlab platform.
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kinetics of chemokine glycosaminoglycan interactions control neutrophil migration into the airspaces of the lungs
Journal of Immunology, 2010Co-Authors: Yoshi Tanino, Amanda E. I. Proudfoot, Deirdre R Coombe, Sean E Gill, Warren C Kett, Osamu Kajikawa, Timothy Wells, William C Parks, Thomas N Wight, Thomas R MartinAbstract:Chemokine–glycosaminoglycan (GAG) interactions are thought to result in the formation of tissue-bound chemokine gradients. We hypothesized that the binding of Chemokines to GAGs would increase neutrophil migration toward CXC Chemokines instilled into lungs of mice. To test this hypothesis we compared neutrophil migration toward recombinant human CXCL8 (rhCXCL8) and two mutant forms of CXCL8, which do not bind to heparin immobilized on a sensor chip. Unexpectedly, when instilled into the lungs of mice the CXCL8 mutants recruited more neutrophils than rhCXCL8. The CXCL8 mutants appeared in plasma at significantly higher concentrations and diffused more rapidly across an extracellular matrix in vitro. A comparison of the murine CXC Chemokines, KC and MIP-2, revealed that KC was more effective in recruiting neutrophils into the lungs than MIP-2. KC appeared in plasma at significantly higher concentrations and diffused more rapidly across an extracellular matrix in vitro than MIP-2. In kinetic binding studies, KC, MIP-2, and rhCXCL8 bound heparin differently, with KC associating and dissociating more rapidly from immobilized heparin than the other Chemokines. These data suggest that the kinetics of chemokine–GAG interactions contributes to chemokine function in tissues. In the lungs, it appears that Chemokines, such as CXCL8 or MIP-2, which associate and disassociate slowly from GAGs, form gradients relatively slowly compared with Chemokines that either bind GAGs poorly or interact with rapid kinetics. Thus, different types of chemokine gradients may form during an inflammatory response. This suggests a new model, whereby GAGs control the spatiotemporal formation of chemokine gradients and neutrophil migration in tissue.
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hiv 1 tat protein mimicry of Chemokines
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Adriana Albini, Amanda E. I. Proudfoot, Timothy N C Wells, Silvano Ferrini, Roberto Benelli, Sabrina Sforzini, Daniela Giunciuglio, M G Aluigi, Sami Alouani, Giuliano MarianiAbstract:The HIV-1 Tat protein is a potent chemoattractant for monocytes. We observed that Tat shows conserved amino acids corresponding to critical sequences of the Chemokines, a family of molecules known for their potent ability to attract monocytes. Synthetic Tat and a peptide (CysL24–51) encompassing the “chemokine-like” region of Tat induced a rapid and transient Ca2+ influx in monocytes and macrophages, analogous to β-Chemokines. Both monocyte migration and Ca2+ mobilization were pertussis toxin sensitive and cholera toxin insensitive. Cross-desensitization studies indicated that Tat shares receptors with MCP-1, MCP-3, and eotaxin. Tat was able to displace binding of β-Chemokines from the β-chemokine receptors CCR2 and CCR3, but not CCR1, CCR4, and CCR5. Direct receptor binding experiments with the CysL24–51 peptide confirmed binding to cells transfected with CCR2 and CCR3. HIV-1 Tat appears to mimic β-chemokine features, which may serve to locally recruit chemokine receptor-expressing monocytes/macrophages toward HIV producing cells and facilitate activation and infection.
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glycosaminoglycans mediate cell surface oligomerization of Chemokines
Biochemistry, 1997Co-Authors: Arlene J Hoogewerf, Amanda E. I. Proudfoot, Gabriele S V Kuschert, Frederic Borlat, Ian Clarklewis, Christine A Power, Timothy N C WellsAbstract:Chemokines are 8−10 kDa proteins involved in the control of leukocyte trafficking and activation. In free solution, Chemokines are monomers at physiologic concentrations, although many multimerize at higher concentrations. Cell surface heparan sulfate may sequester Chemokines, increasing their local concentrations and facilitating their binding to receptors expressed on leukocytes. In competitive binding assays using immobilized heparin, a 2−3-fold increase in the bound radiolabeled chemokine was seen with increasing concentrations of unlabeled chemokine in the nanomolar range. Unlabeled chemokine concentrations between 0.25 and 50 μM were needed to compete the bound radioactivity. This biphasic competition curve was not seen for N-methyl-L25 IL-8, a variant of IL-8 which is unable to dimerize. In addition, complexes of chemokine and heparin eluted from gel filtration columns with apparent molecular masses of 33−60 kDa, suggesting that chemokine multimerization had occurred. The physiological relevance of...
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glycosaminoglycans mediate cell surface oligomerization of Chemokines
Biochemistry, 1997Co-Authors: Arlene J Hoogewerf, Amanda E. I. Proudfoot, Gabriele S V Kuschert, Frederic Borlat, Ian Clarklewis, Christine A Power, Timothy N C WellsAbstract:Chemokines are 8-10 kDa proteins involved in the control of leukocyte trafficking and activation. In free solution, Chemokines are monomers at physiologic concentrations, although many multimerize at higher concentrations. Cell surface heparan sulfate may sequester Chemokines, increasing their local concentrations and facilitating their binding to receptors expressed on leukocytes. In competitive binding assays using immobilized heparin, a 2-3-fold increase in the bound radiolabeled chemokine was seen with increasing concentrations of unlabeled chemokine in the nanomolar range. Unlabeled chemokine concentrations between 0.25 and 50 microM were needed to compete the bound radioactivity. This biphasic competition curve was not seen for N-methyl-L25 IL-8, a variant of IL-8 which is unable to dimerize. In addition, complexes of chemokine and heparin eluted from gel filtration columns with apparent molecular masses of 33-60 kDa, suggesting that chemokine multimerization had occurred. The physiological relevance of this multimerization process was seen from studies using human endothelial cells. The endothelial cell binding sites for IL-8, RANTES, and MCP-1 were deduced to be glycosaminoglycans since competition assays showed the biphasic curves and micromolar IC50 values seen in studies with immobilized heparin, and mRNA for known chemokine receptors was not detected. Furthermore, digestion of endothelial cell monolayers with glycosaminidases decreased chemokine binding by up to 80%. Glycosaminoglycans can act as modulators of the ligand binding affinity of chemokine receptor-bearing cells. Removal of glycosaminoglycans from CHO cells expressing chemokine receptors CXCR1, CCR1, or CCR2 resulted in 40-70% decreases in the binding of RANTES, MCP-1, IL-8, and MIP-1alpha. Our data show that cell surface glycosaminoglycans induce polymerization of Chemokines, increasing their local concentration and therefore enhancing their effects on high-affinity receptors within the local microenvironment.
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effect of a cc chemokine receptor antagonist on collagen induced arthritis in dba 1 mice
Immunology Letters, 1997Co-Authors: Platerzyberk Christine, Amanda E. I. Proudfoot, Arlene J Hoogewerf, Christine A Power, Timothy N C WellsAbstract:Chemokines are small proteins that selectively activate and recruit leukocytes to sites of inflammation. Several of them, including the CC Chemokines RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and the CXC Chemokines IL-8, GRO-alpha, ENA-78 have been identified in rheumatoid synovium, implicating a potential role for these molecules in rheumatoid arthritis. We have investigated the expression patterns of CC chemokine receptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration of MetRANTES, a modified chemokine which is a nanomolar antagonist of certain CC chemokine receptors. The mRNA expression pattern of the Chemokines and their receptors in the joints of arthritic mice was investigated using reverse transcriptase-PCR and in situ hybridization. An upregulation of the CC chemokine receptors mCCR1, mCCR2; mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control animals. In addition, injections of MetRANTES reduced the incidence of disease in a dose dependent manner. Furthermore, in MetRANTES-treated mice that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstrate a role for CC Chemokines and their receptors in inflammatory joint destruction and support the use of chemokine receptor antagonists as potential tools to control inflammatory diseases such as rheumatoid arthritis.