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Journal articles on the topic 'CXCR2 receptors'
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1
Hou, Zhi-Shuai, Hong-Kui Zhao, Pedro Perdiguero, Meng-Qun Liu, Kai-Wen Xiang, Chu Zeng, Zhao Li, et al. "Pleiotropic Role of Rainbow Trout CXCRs in Response to Disease and Environment: Insights from Transcriptional Signatures and Structure Analysis." Biomolecules 14, no. 3 (March 12, 2024): 337. http://dx.doi.org/10.3390/biom14030337.
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Chemokines are cytokines with chemoattractant capacities that exert their physiological functions through the binding of chemokine receptors. Thus, chemokine and receptor complexes exert important roles in regulating development and homeostasis during routine immune surveillance and inflammation. Compared to mammals, the physiology and structure of chemokine receptors in fish have not been systematically studied. Furthermore, the salmonid-specific whole genome duplication has significantly increased the number of functional paralogs of chemokine receptors. In this context, in the current study, trout exhibited 17 cxcr genes, including 12 newly identified and 5 previously identified receptors. Interestingly, gene expression of brain cxcr1 and cxcr4, kidney cxcr3 and cxcr4, and spleen cxcr3, cxcr4, and cxcr5 subtypes were altered by bacterial infection, whereas brain cxcr1, kidney cxcr1 and cxcr7, and liver cxcr2, cxcr3, and cxcr4 subtypes were changed in response to environmental changes. Based on protein structures predicted by ColabFold, the conserved amino acids in binding pockets between trout CXCR4.1 subtypes and human CXCR4 were also analyzed. Our study is valuable from a comparative point of view, providing new insights into the identification and physiology of salmonid chemokine receptors.
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Korbecki, Jan, Klaudyna Kojder, Patrycja Kapczuk, Patrycja Kupnicka, Barbara Gawrońska-Szklarz, Izabela Gutowska, Dariusz Chlubek, and Irena Baranowska-Bosiacka. "The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature." International Journal of Molecular Sciences 22, no. 2 (January 15, 2021): 843. http://dx.doi.org/10.3390/ijms22020843.
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Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors—CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (Tregs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.
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Doroshenko, Tatyana, Yuri Chaly, Valery Savitskiy, Olga Maslakova, Anna Portyanko, Irina Gorudko, and Nikolai N. Voitenok. "Phagocytosing neutrophils down-regulate the expression of chemokine receptors CXCR1 and CXCR2." Blood 100, no. 7 (October 1, 2002): 2668–71. http://dx.doi.org/10.1182/blood.100.7.2668.
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CXC chemokines play a central role in regulation of neutrophil activation and chemotaxis. Because the chemotactic responses of neutrophils are impaired after phagocytosis, we explored the effect of phagocytic stimuli on the expression of interleukin-8 (IL-8) receptors, CXCR1 and CXCR2, in human neutrophils. After phagocytosis of opsonized yeast, the expression of CXCR1 and CXCR2 was substantially down-regulated and was accompanied by reduced Ca++responses to corresponding ligands, IL-8 and neutrophil-activating peptide–2 (NAP-2). The levels of CXCR1 and CXCR2 mRNA were constant during phagocytic stimulation of neutrophils. Confocal microscopy revealed that CXCR reduction was not via internalization. Metalloproteinase inhibitor, 1,10-phenantroline, prevented the reduction of CXCRs induced by phagocytosis, indicating that proteolytic degradation may be responsible for down-regulation. These observations suggest that down-regulation of CXCR expression may substantially reduce the responsiveness of phagocytosing neutrophils to CXC chemokines.
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Lepsenyi, Mattias, Nader Algethami, Amr A. Al-Haidari, Anwar Algaber, Ingvar Syk, Milladur Rahman, and Henrik Thorlacius. "CXCL2-CXCR2 axis mediates αV integrin-dependent peritoneal metastasis of colon cancer cells." Clinical & Experimental Metastasis 38, no. 4 (June 11, 2021): 401–10. http://dx.doi.org/10.1007/s10585-021-10103-0.
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AbstractPeritoneal metastasis is an insidious aspect of colorectal cancer. The aim of the present study was to define mechanisms regulating colon cancer cell adhesion and spread to peritoneal wounds after abdominal surgery. Mice was laparotomized and injected intraperitoneally with CT-26 colon carcinoma cells and metastatic noduli in the peritoneal cavity was quantified after treatment with a CXCR2 antagonist or integrin-αV-antibody. CT-26 cells expressed cell surface chemokine receptors CXCR2, CXCR3, CXCR4 and CXCR5. Stimulation with the CXCR2 ligand, CXCL2, dose-dependently increased proliferation and migration of CT-26 cells in vitro. The CXCR2 antagonist, SB225002, dose-dependently decreased CXCL2-induced proliferation and migration of colon cancer cells in vitro. Intraperitoneal administration of CT-26 colon cancer cells resulted in wide-spread growth of metastatic nodules at the peritoneal surface of laparotomized animals. Laparotomy increased gene expression of CXCL2 at the incisional line. Pretreatment with CXCR2 antagonist reduced metastatic nodules by 70%. Moreover, stimulation with CXCL2 increased CT-26 cell adhesion to extracellular matrix (ECM) proteins in a CXCR2-dependent manner. CT-26 cells expressed the αV, β1 and β3 integrin subunits and immunoneutralization of αV abolished CXCL2-triggered adhesion of CT-26 to vitronectin, fibronectin and fibrinogen. Finally, inhibition of the αV integrin significantly attenuated the number of carcinomatosis nodules by 69% in laparotomized mice. These results were validated by use of the human colon cancer cell line HT-29 in vitro. Our data show that colon cancer cell adhesion and growth on peritoneal wound sites is mediated by a CXCL2-CXCR2 signaling axis and αV integrin-dependent adhesion to ECM proteins.
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Konrad, F. M., and J. Reutershan. "CXCR2 in Acute Lung Injury." Mediators of Inflammation 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/740987.
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In pulmonary inflammation, recruitment of circulating polymorphonuclear leukocytes is essential for host defense and initiates the following specific immune response. One pathological hallmark of acute lung injury and acute respiratory distress syndrome is the uncontrolled transmigration of neutrophils into the lung interstitium and alveolar space. Thereby, the extravasation of leukocytes from the vascular system into the tissue is induced by chemokines that are released from the site of inflammation. The most relevant chemokine receptors of neutrophils are CXC chemokine receptor (CXCR) 1 and CXCR2. CXCR2 is of particular interest since several studies implicate a pivotal role of this receptor in development and promotion of numerous inflammatory disorders. CXCR2 gets activated by ELR+chemokines, including MIP-2, KC (rodents) and IL-8 (human). Since multiple ELR+CXC chemokines act on both receptors—CXCR1 and CXCR2—a pharmacologic agent blocking both receptors seems to be advantageous. So far, several CXCR1/2 antagonists have been developed and have been tested successfully in experimental studies. A newly designed CXCR1 and CXCR2 antagonist can be orally administered and was for the first time found efficient in humans. This review highlights the role of CXCR2 in acute lung injury and discusses its potential as a therapeutic target.
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Uhl, Barbara, Katharina T. Prochazka, Katrin Pansy, Kerstin Wenzl, Johanna Strobl, Claudia Baumgartner, Marta M. Szmyra, et al. "Distinct Chemokine Receptor Expression Profiles in De Novo DLBCL, Transformed Follicular Lymphoma, Richter’s Trans-Formed DLBCL and Germinal Center B-Cells." International Journal of Molecular Sciences 23, no. 14 (July 17, 2022): 7874. http://dx.doi.org/10.3390/ijms23147874.
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Chemokine receptors and their ligands have been identified as playing an important role in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and Richter syndrome (RS). Our aim was to investigate the different expression profiles in de novo DLBCL, transformed follicular lymphoma (tFL), and RS. Here, we profiled the mRNA expression levels of 18 chemokine receptors (CCR1–CCR9, CXCR1–CXCR7, CX3CR1 and XCR1) using RQ-PCR, as well as immunohistochemistry of seven chemokine receptors (CCR1, CCR4–CCR8 and CXCR2) in RS, de novo DLBCL, and tFL biopsy-derived tissues. Tonsil-derived germinal center B-cells (GC-B) served as non-neoplastic controls. The chemokine receptor expression profiles of de novo DLBCL and tFL substantially differed from those of GC-B, with at least 5-fold higher expression of 15 out of the 18 investigated chemokine receptors (CCR1–CCR9, CXCR1, CXCR2, CXCR6, CXCR7, CX3CR1 and XCR1) in these lymphoma subtypes. Interestingly, the de novo DLBCL and tFL exhibited at least 22-fold higher expression of CCR1, CCR5, CCR8, and CXCR6 compared with RS, whereas no significant difference in chemokine receptor expression profile was detected when comparing de novo DLBCL with tFL. Furthermore, in de novo DLBCL and tFLs, a high expression of CCR7 was associated with a poor overall survival in our study cohort, as well as in an independent patient cohort. Our data indicate that the chemokine receptor expression profile of RS differs substantially from that of de novo DLBCL and tFL. Thus, these multiple dysregulated chemokine receptors could represent novel clinical markers as diagnostic and prognostic tools. Moreover, this study highlights the relevance of chemokine signaling crosstalk in the tumor microenvironment of aggressive lymphomas.
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Coperchini, Francesca, Laura Croce, Michele Marinò, Luca Chiovato, and Mario Rotondi. "Role of chemokine receptors in thyroid cancer and immunotherapy." Endocrine-Related Cancer 26, no. 8 (August 2019): R465—R478. http://dx.doi.org/10.1530/erc-19-0163.
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Inflammation is currently regarded as an essential component of malignancies. It is now known that the tumor microenvironment may profoundly influence the biological behavior of cancer cells and ultimately the patient’s outcome. Chemokine and their receptor play a major role in determining the immune phenotype of the cells infiltrating the thyroid tumor microenvironment. Experimental evidence shows that both normal and cancer thyroid cells express specific chemokine receptors. The expression of at least some of these receptors exerts several biological effects, which influence the course of the disease. The present review article will take into account the role of the most studied chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, DARC, CCR3, CCR6 and CCR7) in the context of thyroid cancer. This review will focus on current knowledge provided by in vitro and in vivo studies specifically performed on thyroid cancer including (i) expression of chemokine receptors in normal and cancer thyroid cells; (ii) role of chemokine receptors in affecting the biological behavior of thyroid tumors including the metastatic process; (iii) current knowledge about immunotherapies through targeting of chemokine receptors in thyroid cancer.
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Daniele, Simona, Simona Saporiti, Stefano Capaldi, Deborah Pietrobono, Lara Russo, Uliano Guerrini, Tommaso Laurenzi, et al. "Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence." International Journal of Molecular Sciences 24, no. 1 (December 23, 2022): 261. http://dx.doi.org/10.3390/ijms24010261.
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GPR17, a G protein-coupled receptor, is a pivotal regulator of myelination. Its endogenous ligands trigger receptor desensitization and downregulation allowing oligodendrocyte terminal maturation. In addition to its endogenous agonists, GPR17 could be promiscuously activated by pro-inflammatory oxysterols and chemokines released at demyelinating lesions. Herein, the chemokine receptors CXCR2 and CXCR4 were selected to perform both in silico modelling and in vitro experiments to establish their structural and functional interactions with GPR17. The relative propensity of GPR17 and CXCR2 or CXCR4 to form homo- and hetero-dimers was assessed by homology modelling and molecular dynamics (MD) simulations, and co-immunoprecipitation and immunoenzymatic assay. The interaction between chemokine receptors and GPR17 was investigated by determining receptor-mediated modulation of intracellular cyclic adenosine monophosphate (cAMP). Our data show the GPR17 association with CXCR2 or CXCR4 and the negative regulation of these interactions by CXCR agonists or antagonists. Moreover, GPR17 and CXCR2 heterodimers can functionally influence each other. In contrast, CXCR4 can influence GPR17 functionality, but not vice versa. According to MD simulations, all the dimers reached conformational stability and negative formation energy, confirming the experimental observations. The cross-talk between these receptors could play a role in the development of the neuroinflammatory milieu associated with demyelinating events.
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Zhang, Jing, Shouguo Huang, Lini Quan, Qiu Meng, Haiyan Wang, Jie Wang, and Jin Chen. "Determination of Potential Therapeutic Targets and Prognostic Markers of Ovarian Cancer by Bioinformatics Analysis." BioMed Research International 2021 (March 19, 2021): 1–13. http://dx.doi.org/10.1155/2021/8883800.
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This study is to study the expression of CXCRs in ovarian cancer tissues and their value in prognosis. The expressions of CXCR1-CXCR7 mRNA between ovarian tumor tissues and normal tissues and in different pathological types of ovarian tumor tissues were compared by ONCOMINE online tool. The relationship between the expression of CXCRs and clinical pathological staging was studied by GEPIA. Kaplan-Meier plotter online tool was used to analyze prognosis. Finally, GO and KEGG analyses and protein interaction network analysis were performed for CXCRs by the DAVID software to predict their function, and cBioPortal was used to identify the key functional genes. The expression of CXCR3/4/7 mRNA in ovarian cancer tissues was higher than that in normal ovarian tissues, and the expression of CXCR4 was the highest ( fold change = 306.413 , P < 0.05 ). The expression of CXCR1/2/3/4/7 mRNA in different pathological types of ovarian tumors was significantly different ( P < 0.05 ). Only CXCR5 expression level was associated with tumor staging. Survival analysis showed that high CXCR7 mRNA expression and low CXCR5/6 expression were associated with the shortening of overall survival. High CXCR4/7 expression and low CXCR5/6 expression were associated with the shortening of progression-free survival. High CXCR2/4 expression and low CXCR5/6 expression were closely related to the shortening of postprogressing survival. Protein interaction network analysis showed that GNB1, PTK2, MAPK1, PIK3CA, GNB4, GNA11, KNG1, and ARNT proteins were closely related to the CXC receptor family. CXCR3/4/7 are potential therapeutic targets, and CXCR2/4/5/6/7 are new markers for the prognosis of ovarian cancer.
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Inngjerdingen, Marit, Bassam Damaj, and Azzam A. Maghazachi. "Expression and regulation of chemokine receptors in human natural killer cells." Blood 97, no. 2 (January 15, 2001): 367–75. http://dx.doi.org/10.1182/blood.v97.2.367.
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Abstract Using flow cytometric and RNase protection assays, this study examined the expression of chemokine receptors in nonactivated natural killer (NK) cells and compared this expression with NK cells activated with interleukin (IL)-2, which either adhered to plastic flasks (AD) or did not adhere (NA). None of the NK cell subsets expressed CXCR2, CXCR5, or CCR5. The major differences between these cells include increased expression of CXCR1, CCR1, CCR2, CCR4, CCR8, and CX3CR1 in AD when compared to NA or nonactivated NK cells. The chemotactic response to the CXC and CC chemokines correlated with the receptor expression except that all 3 populations responded to GRO-α, despite their lack of CXCR2 expression. Pretreatment of these cells with anti-CXCR2 did not inhibit the chemotactic response to GRO-α. In addition, nonactivated and NA cells responded to fractalkine, although they lack the expression of CX3CR1. This activity was not inhibited by anti-CX3CR1. Viral macrophage inflammatory protein (vMIP)-I, I-309, and TARC competed with the binding of 125I-309 to AD cells with varying affinities. Transforming growth factor (TGF)-β1 but not any other cytokine or chemokine examined including interferon (IFN)-γ, MIP-3β, macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC) or I-309, up-regulated the expression of CXCR3 and CXCR4 on NK cell surface. This is correlated with increased chemotaxis of NK cells treated with TGF-β1 toward stromal cell–derived factor (SDF)-1α and interferon-inducible protein-10 (IP-10). Messenger RNA for lymphotactin, RANTES, MIP-1α, and MIP-1β, but not IP-10, monocyte chemotactic protein (MCP)-1, IL-8, or I-309 was expressed in all 3 NK cell subsets. Our results may have implications for the dissemination of NK cells at the sites of tumor growth or viral replication.
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Schmausser, Bernd, Christine Josenhans, Simon Endrich, Sebastian Suerbaum, Cassian Sitaru, Mindaugas Andrulis, Stephanie Brändlein, Peter Rieckmann, Hans Konrad Müller-Hermelink, and Matthias Eck. "Downregulation of CXCR1 and CXCR2 Expression on Human Neutrophils by Helicobacter pylori: a New Pathomechanism in H. pylori Infection?" Infection and Immunity 72, no. 12 (December 2004): 6773–79. http://dx.doi.org/10.1128/iai.72.12.6773-6779.2004.
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ABSTRACT In Helicobacter pylori gastritis, neutrophil activation and migration, which play central roles in the pathogenesis of the disease, are regulated by the neutrophil attractant chemokines interleukin 8 (IL-8) and Groα, whose secretion is induced by H. pylori. However, the modulation of the corresponding chemokine receptors CXCR1 and CXCR2 on human neutrophils under the influence of H. pylori has not been investigated. Incubation of neutrophils with cag + and cag deletion H. pylori strains resulted in a complete downregulation of the CXCR1 and the CXCR2 receptors after 0.5 h, as tested by fluorescence-activated cell sorter analysis, independent of the cag status. Downregulation of CXCR1 and CXCR2 seems to occur via receptor internalization and rapid degradation, as shown by confocal microscopy and immunoblotting. Neither the proinflammatory cytokines IL-8 and tumor necrosis factor alpha produced by the neutrophils themselves nor H. pylori lipopolysaccharide, which are the known regulators of these two chemokine receptors, was responsible for the downregulation. Reverse transcription-PCR analysis showed that CXCR1 and CXCR2 mRNAs of neutrophils were reduced at a later time than the CXCR1 and CXCR2 proteins. Moreover, cag + H. pylori strains induced significantly stronger downregulation of CXCR1 and CXCR2 mRNAs than the cag deletion mutant. Therefore, receptor protein and mRNA downregulation seem to be mediated by two independent mechanisms. Data obtained by immunohistochemistry suggested that downmodulation of CXCR1 and CXCR2 on neutrophils may also occur in vivo in the human stomach during H. pylori infection. Downregulation of CXCR1 and CXCR2 expression on neutrophils in H. pylori infection by H. pylori itself may represent a new mechanism of modulating neutrophil migration and activation in the gastric mucosa.
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Richardson, Micheler, Timothy Adekoya, Nikia Smith, and Parag Kothari. "Opposite effects of CXCR1 and CXCR2 overexpression in prostate tumorigenesis." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 178.12. http://dx.doi.org/10.4049/jimmunol.208.supp.178.12.
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Abstract Chemokines and their receptors play important role in tumor progression and metastasis. In prostate cancer (PCa), some members of the CXC chemokine receptor have been shown to enhance angiogenesis, proliferation and metastasis. In this study we assess the roles of the interleukin-8 (IL-8/CXCL8) receptors CXCR1 and CXCR2 in prostate tumorigenesis, using MDA PCa 2b and LNCaP cell lines. Our results show that overexpression of CXCR2 enhanced in-vitro cell proliferation, soft agar growth and in-vivo tumor xenograft in nude mice, whereas overexpression of CXCR1 inhibited cell proliferation and tumor growth, relative to control cells. CXCR1 cells showed decrease prostate specific antigen (PSA) expression whereas CXCR2 exhibited decrease androgen receptor (AR) expression. Interestingly, tumor lysates from CXCR1 cells displayed significant increase in ERK and AKT activation as well as chemokines production relative to control and CXCR2 tumors. CXCR1 tumors also exhibited a more mesenchymal phenotype, characterized by reduced E-Cadherin but increased N-Cadherin and Vimentin expression relative to CXCR2 or control tumors. Altogether, these results indicate that CXCR1 and CXCR2 may couple to distinct pathways to modulate prostate tumorigenesis. Supported by CA156735, MD012392
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Таганович, А. Д., Н. Н. Ковганко, В. И. Прохорова, О. В. Готько, Л. А. Державец, and Д. И. Мурашко. "Chemokines CXCL5, CXCL8 and Their Receptors CXCR1, CXCR2 as Potential Biomarkers of Non-Small Cell Lung Cancer." Лабораторная диагностика. Восточная Европа, no. 3 (October 20, 2020): 252–71. http://dx.doi.org/10.34883/pi.2020.9.3.007.
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Цель. Изыскание новых биомаркеров немелкоклеточного рака легкого (НМРЛ) на основе определения концентрации хемокинов CXCL5 и CXCL8 в сыворотке крови, содержания и плотности их рецепторов CXCR1 и CXCR2 в клетках крови пациентов с НМРЛ, гамартомой легкого и здоровых людей.Материалы и методы. Материалом служила кровь 110 пациентов с НМЛР, 13 человек с гамартомой (доброкачественной опухолью) легкого и 30 здоровых людей. Концентрацию CXCL5, CXCL8 определяли в сыворотке крови методом ИФА. Уровень рецепторов CXCR1, CXCR2 определяли в клетках крови методом проточной цитометрии.Результаты и обсуждение. Доказывается, что содержание хемокинов CXCL5, CXCL8 в периферической крови и соответствующих рецепторов CXCR1, CXCR2 в клетках крови пациентов с НМРЛ значительно превышает их уровень у здоровых людей и пациентов с гамартомой легкого, что позволяет считать причиной выявленных изменений молекулярные события злокачественного роста. Показано, что со стадиями заболевания наиболее тесно связано изменение уровня CXCL5 в плазме (сыворотке) крови, относительное количество лимфоцитов, снабженных рецепторами CXCR1 и CXCR2, в общем количестве этих клеток и плотность рецепторов CXCR2 на лимфоцитах и моноцитах. С наличием отдаленных метастазов связана плотность рецепторов CXCR2 на лимфоцитах; со степенью злокачественности опухоли – плотность рецепторов CXCR2 на гранулоцитах.Заключение. Определение концентрации CXCL5 и CXCL8, плотности рецепторов CXCR1 на гранулоцитах весьма перспективно для осуществления дифференциальной диагностики ранних (I, II) и поздних (III, IV) стадий НМРЛ, поскольку используемые для этого тесты обладают большей диагностической чувствительностью и диагностической специфичностью (при определенных, полученных с помощью ROC-анализа пороговых значениях), чем тест определения CYFRA 21-1. Аналогичное преимущество имеет определение плотности рецепторов CXCR2 на гранулоцитах для диагностирования размеров опухоли и наличия метастазов. Измерение плотности рецепторов CXCR1 и CXCR2 на гранулоцитах в периферической крови пациентов с НМРЛ предпочтительно для суждения о степени злокачественности опухоли. Purpose. The search for new biomarkers of non-small cell lung cancer (NSCLC) based on the determination of the serum chemokines CXCL5 and CXCL8, their receptors CXCR1 and CXCR2 in the blood cells of patients with NSCLC, lung hamartoma, and healthy people.Materials and methods. The material was the blood of 110 patients with NSCLC, 13 people with lung hamartoma, and 30 healthy people. The concentration of CXCL5, CXCL8 was determined in blood serum with the help of ELISA. The level of receptors CXCR1, CXCR2 was determined in blood cells with the help of flow cytometry.Results and discussion. It is proved that the level of chemokines CXCL5, CXCL8 in the peripheral blood and their receptors CXCR1, CXCR2 in blood cells of patients with NSCLC is significantly higher than their level in healthy people and patients with lung hamartoma, which indicates that the sources of these changes are the molecular events of malignant growth tumors. It was showed that the level of serum CXCL5, the relative number of lymphocytes in the total number of these cells with CXCR1 and CXCR2 receptors, and the density of CXCR2 receptors on lymphocytes and monocytes are most closely associated with the stages of the disease. The presence of distant metastases is associated with the density of CXCR2 receptors on lymphocytes; the density of CXCR2 receptors on granulocytes – with the degree of tumor malignancy.Conclusion. Determination of the concentration of CXCL5 and CXCL8, the density of CXCR1 receptors on granulocytes in the differential diagnostics of the early (I, II) and late (III, IV) stages of NSCLC has better diagnostic sensitivity and diagnostic specificity for threshold values obtained using ROC-analysis than using CYFRA 21-1 for this purpose. A similar advantage is the determination of the density of CXCR2 receptors on granulocytes for diagnostics of tumor size and the presence of metastases. Measurement of the density of CXCR1 and CXCR2 receptors on granulocytes in the peripheral blood of patients with NSCLC is preferable to assess the degree of tumor malignancy.
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Litman-Zawadzka, Ala, Marta Łukaszewicz-Zając, Mariusz Gryko, Agnieszka Kulczyńska-Przybik, Bogusław Kędra, and Barbara Mroczko. "Specific Receptors for the Chemokines CXCR2 and CXCR4 in Pancreatic Cancer." International Journal of Molecular Sciences 21, no. 17 (August 27, 2020): 6193. http://dx.doi.org/10.3390/ijms21176193.
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Background: The mortality rate of pancreatic cancer (PC) is equal to its incidence and the majority of PC patients die within a few months of diagnosis. Therefore, a search for new biomarkers useful in the diagnosis and prognosis of PC is ongoing. Objectives: The aim of our study was to compare the utility of CXCR2 and CXCR4 in the diagnosis and prediction of PC with classical tumor marker (carcinoembryonic antigen, CEA) and marker of inflammation–C-reactive protein (CRP). Patients and Methods: The study comprised 64 subjects — 32 PC patients and 32 healthy volunteers. Serum concentrations of tested proteins were analysed using immunological methods. Results: Serum CXCR2 and CXCR4 concentrations, similarly to those of CEA and CRP, were significantly elevated in PC patients compared to healthy controls. Moreover, concentrations of CXCR4 were significantly correlated with CXCR2 and CRP levels, while CRP concentrations were correlated with CXCR2 and CEA levels. The diagnostic sensitivity and the predictive value for negative (PV−ve) results for CXCR4 were similar to those of CEA and higher than those of CXCR2 and CRP, while the area under the ROC curve (AUC) for CXCR4 was the highest among all tested proteins (CXCR2, CEA, CRP). Moreover, serum CXCR2 was found to be a significant predictor of PC risk. Conclusions: CXCR4 is a better candidate for a tumor marker than CXCR2 in the diagnosis of PC, while serum CXCR2 is a significant predictor of PC risk.
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Yildirim, Sedat, Frank Bautz, Andreas M. Boehmler, Lothar Kanz, and Robert Möhle. "Regulation of CXCR1, CXCR2 and CXCR4 in Human Neutrophils: Potential Role in the Release from the Bone Marrow, Clearance of Senescent Cells, and Cell Function at Sites of Inflammation." Blood 106, no. 11 (November 16, 2005): 3068. http://dx.doi.org/10.1182/blood.v106.11.3068.3068.
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Abstract In the mouse model, it has been shown that the interleukin-8 (IL-8) receptor CXCR2 is involved in the release of mature neutrophils from the bone marrow into the circulation. When neutrophils age, upregulation of CXCR4 and downmodulation of CXCR2 result in homing and subsequent sequestration of senescent cells in the bone marrow. In our study, we observed a similar time-dependent (starting at 3 hrs., maximum at 12–18 hrs.) downregulation of CXCR2 in human neutrophils during aging in ex vivo culture, while expression of the second IL-8 receptor CXCR1, which is mainly responsible for the IL-8-induced chemotaxis, was unchanged. Furthermore, strong upregulation of CXCR4 was noted on the cell surface which could not solely be attributed to re-expression of internalized, intracellular receptors, as an increased amount of CXCR4 mRNA was detected by Northern blot analysis in these cells. The increase in CXCR4 expression was not influenced by inflammatory cytokines such as TNF and IL-1, as well as by IL-8 or G-CSF. Accordingly, SDF-1-induced transendothelial migration of aged neutrophils was 6-fold increased and even exceeded migration in response to IL-8. We conclude that also in human neutrophils, loss of CXCR2 and gain of CXCR4 expression on the cell surface may favor homing and sequestration of senescent cells in the bone marrow. At sites of inflammation however, retained expression of CXCR1 and increased expression of CXCR4 still allow a response of aged, pre-apoptotic neutrophils to the chemotactic mediators IL-8 and SDF-1, as the latter is not only released in the bone marrow, but also at sites of tissue damage and necrosis.
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Davies, Faith E., Mona H. Al Rayes, J. Anthony Child, Gareth J. Morgan, and Andrew C. Rawstron. "The Bone Marrow Microenvironment Influences the Differential Chemokine Receptor Expression of Normal and Neoplastic Plasma Cells." Blood 104, no. 11 (November 16, 2004): 2353. http://dx.doi.org/10.1182/blood.v104.11.2353.2353.
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Abstract The expression of cytokines and chemokines are under control of several factors, including the bone marrow (BM) microenvironment. The aim of this work was to study the chemokine receptor expression on normal and neoplastic PCs and to investigate the relationship between the BM microenvironment and plasma cell behaviour. The study included 20 patients with reactive disorders or normal BM, 20 individuals with MGUS (monoclonal gammopathy of undetermined significance) and 19 patients with multiple myeloma at presentation. A large panel of chemokine receptor-specific antibodies directed against CCR1, CCR2, CCR3, CCR5, CCR6, CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 was characterized employing a four-colour flow cytometry approach. We demonstrate that normal and myeloma PCs have a specific chemokine receptor profile expressing 7/10 of the receptors studied. CCR2, CCR6, and CXCR1 showed decreased expression on myeloma PCs in comparison to normal PCs (average 3.3, 1.5 and 1.8-fold difference in expression level respectively). In contrast CXCR4 was upregulated on myeloma PCs on average 2.2-fold in comparison to normal PCs. There was no significant difference in expression between normal (CD19+) and neoplastic (CD19−) PCs from the same bone marrow environment in MGUS patients with respect to CCR6, CXCR1 and CXCR4. In contrast there was a significant difference in expression of CCR2 between CD19+ and CD19− PCs from the same BM (P=0.002). The level of expression on CD19− PCs was on average 1.6-fold lower than on their CD19+ counterparts (range 1.1 6.8-fold lower). In conclusion these data demonstrate that normal and myeloma PCs have a specific chemokine receptor profile. Myeloma PCs have a reduced level of some chemokine receptors compared to normal PCs which may account for their abnormal localization within the BM. Differences in expression of CXCR1, CXCR4, and CCR6 are not specific to the neoplastic process, as both normal and neoplastic plasma cells from the same marrow in MGUS patients show corresponding levels of expression. It is probable that feedback loops between neoplastic plasma cells and bone marrow stroma also influence normal plasma cell expression of these chemokine receptors. However, differences in CCR2 expression are not influenced by the marrow microenvironment, therefore downregulation of CCR2 expression is either a function of the neoplastic process or of the stage of differentiation of the originating neoplastic cell. Interfering with chemokines and their receptors which are related to the malignant transformation, particularly CCR2, may prove useful as adjunct to chemotherapy approaches.
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Lachota, Mieszko, Daniel Alfredo Palacios, Dennis Clement, Eivind Heggernes Ask, Hanna Julie Hoel, Merete Thune Wiiger, Marianna Vincenti, Magdalena Winiarska, Radoslaw Zagozdzon, and Karl-Johan Malmberg. "Innate-like Chemokine Receptor Profile and Migratory Behaviour By Terminally Differentiated and Educated NK Cells." Blood 136, Supplement 1 (November 5, 2020): 24–25. http://dx.doi.org/10.1182/blood-2020-140944.
Full textAbstract:
Natural Killer (NK) cells play an essential role in cancer surveillance and have a unique capability of spontaneous cytotoxicity against cancer cells. The human NK cell repertoire is functionally diversified through a tightly regulated differentiation process characterized by an early transition from CD56bright to CD56dim NK cells, followed by coordinated changes in expression of inhibitory receptors, including NKG2A and killer cell immunoglobulin-like receptors (KIR). The acquisition of self HLA class I binding KIRs during NK cell differentiation tunes the cytotoxic potential of NK cells in a process termed education, characterized by increased loading of granzyme B in dense core granules. Although NK cell differentiation and education are critical determinants of the functional potential of the cell, little is known about how these events shape the migratory behavior of NK cells. To mediate appropriate and directed immune response against cancer, NK cells must be capable of migration to the tumor site. This process is mediated by chemokines, which guide cell migration by binding to their specific receptors. For example, in multiple myeloma, CXCR3 and CCR5 ligands (MIG, IP-10, and MIP-1a) are significantly upregulated in the bone marrow compared to healthy controls, affecting the composition of immune cells in the tumor microenvironment. In order to delineate the homing patterns of distinct NK cell subsets, we used high-dimensional flow cytometry combined with functional assays to map the NK cell chemokine receptor expression and migratory behavior. We screened resting and cytokine/feeder cell stimulated peripheral blood NK cells for the expression of a panel of 20 chemokine receptors (A). Based on CD56, CD57, NKG2A, and KIR expression, NK cells were divided into 6 phenotypically and functionally distinct subsets that were ordered according to their differentiation status (B). We found that the expression of CX3CR1, CXCR1, CXCR2, and CMKLR1 gradually increased during differentiation, whereas the expression of CXCR3, CCR7, and CCR5 was lower in more differentiated NK cells. CXCR4, CCR4, and CCR2 expression was relatively uniform across all subsets. Interestingly, CCR1 and CXCR6 were expressed mainly on less differentiated NKG2A+ CD56dim NK cells (B). Next, we stratified the chemokine receptor expression on mature KIR+ NK cells based on the expression of self (educated) or non-self KIR (uneducated). Educated NK cells expressed CXCR1, CX3CR1, CCR5, and CMKLR1 at higher levels than the uneducated NK cells. Conversely, CXCR3 was expressed at lower levels on educated NK cells (C). No difference was observed for CXCR2 expression. To determine whether the observed differences in chemokine receptor expression translate into altered chemokine responsiveness between the subsets, we combined the transwell system with multicolor flow cytometry. We found that the chemokine-induced migration capability of NK cells correlated closely with the expression level of corresponding chemokine receptor, leading to subset specific responses to various chemokine gradients (D). The present results show that peripheral blood NK cell chemokine receptor profile changes in a coordinated fashion during NK cell differentiation and is further influenced by the expression of self-specific KIR. Interestingly, receptors which expression declines during NK cell differentiation (CCR5, CCR7, and CXCR3) are commonly associated with adaptive T cell responses to viruses, whereas receptors that are upregulated along the differentiation axis (CXCR1, CXCR2, CX3CR1, CMKLR1) are typical for neutrophils and macrophages as a part of the innate immune response. Thus, our results suggest that NK cell differentiation and education processes together shape the NK cell migratory capabilities to promote homing of the most functional NK cell subsets to the site of inflammation and serve as the first line of defense in the immune response to pathogens and tumors. Figure Disclosures Malmberg: Fate Therapeutics: Consultancy, Patents & Royalties; Vycellix: Membership on an entity's Board of Directors or advisory committees.
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Khandaker, Masud H., Gordon Mitchell, Luoling Xu, Joseph D. Andrews, Rajkumari Singh, Harry Leung, Joaquı́n Madrenas, Stephen S. G. Ferguson, Ross D. Feldman, and David J. Kelvin. "Metalloproteinases Are Involved in Lipopolysaccharide– and Tumor Necrosis Factor-–Mediated Regulation of CXCR1 and CXCR2 Chemokine Receptor Expression." Blood 93, no. 7 (April 1, 1999): 2173–85. http://dx.doi.org/10.1182/blood.v93.7.2173.
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Abstract The neutrophil-specific G-protein–coupled chemokine receptors, CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are not well defined, although previous studies have suggested a process of ligand-promoted internalization as a putative regulatory pathway. Herein, we provide evidence for two distinct processes of CXCR1 and CXCR2 regulation. Confocal microscopy data showed a redistribution of CXCR1 expression from the cell surface of neutrophils to internal compartments after stimulation with IL-8, whereas stimulation with bacterial lipopolysaccharide (LPS) or tumor necrosis factor- (TNF-) did not induce CXCR1 internalization but instead mediated a significant loss of membrane-proximal CXCR1 staining intensity. To investigate whether proteolytic cleavage was the mechanism responsible for LPS- and TNF-–induced downmodulation of IL-8 receptors, we tested a panel of proteinase inhibitors. The downmodulation of CXCR1 and CXCR2 by LPS and TNF- was most dramatically inhibited by metalloproteinase inhibitors; 1,10-phenanthroline and EDTA significantly attenuated LPS- and TNF-–induced loss of CXCR1 and CXCR2 cell surface expression. Metalloproteinase inhibitors also blocked the release of CXCR1 cleavage fragments into the cell supernatants of LPS- and TNF-–stimulated neutrophils. In addition, while treatment of neutrophils with LPS and TNF- inhibited IL-8 receptor–mediated calcium mobilization and IL-8–directed neutrophil chemotaxis, both 1,10-phenanthroline and EDTA blocked these inhibitory processes. In contrast, metalloproteinase inhibitors did not affect IL-8–mediated downmodulation of CXCR1 and CXCR2 cell surface expression or receptor signaling. Thus, these findings may provide further insight into the mechanisms of leukocyte regulation during immunologic and inflammatory responses.
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Khandaker, Masud H., Gordon Mitchell, Luoling Xu, Joseph D. Andrews, Rajkumari Singh, Harry Leung, Joaquı́n Madrenas, Stephen S. G. Ferguson, Ross D. Feldman, and David J. Kelvin. "Metalloproteinases Are Involved in Lipopolysaccharide– and Tumor Necrosis Factor-–Mediated Regulation of CXCR1 and CXCR2 Chemokine Receptor Expression." Blood 93, no. 7 (April 1, 1999): 2173–85. http://dx.doi.org/10.1182/blood.v93.7.2173.407a06_2173_2185.
Full textAbstract:
The neutrophil-specific G-protein–coupled chemokine receptors, CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are not well defined, although previous studies have suggested a process of ligand-promoted internalization as a putative regulatory pathway. Herein, we provide evidence for two distinct processes of CXCR1 and CXCR2 regulation. Confocal microscopy data showed a redistribution of CXCR1 expression from the cell surface of neutrophils to internal compartments after stimulation with IL-8, whereas stimulation with bacterial lipopolysaccharide (LPS) or tumor necrosis factor- (TNF-) did not induce CXCR1 internalization but instead mediated a significant loss of membrane-proximal CXCR1 staining intensity. To investigate whether proteolytic cleavage was the mechanism responsible for LPS- and TNF-–induced downmodulation of IL-8 receptors, we tested a panel of proteinase inhibitors. The downmodulation of CXCR1 and CXCR2 by LPS and TNF- was most dramatically inhibited by metalloproteinase inhibitors; 1,10-phenanthroline and EDTA significantly attenuated LPS- and TNF-–induced loss of CXCR1 and CXCR2 cell surface expression. Metalloproteinase inhibitors also blocked the release of CXCR1 cleavage fragments into the cell supernatants of LPS- and TNF-–stimulated neutrophils. In addition, while treatment of neutrophils with LPS and TNF- inhibited IL-8 receptor–mediated calcium mobilization and IL-8–directed neutrophil chemotaxis, both 1,10-phenanthroline and EDTA blocked these inhibitory processes. In contrast, metalloproteinase inhibitors did not affect IL-8–mediated downmodulation of CXCR1 and CXCR2 cell surface expression or receptor signaling. Thus, these findings may provide further insight into the mechanisms of leukocyte regulation during immunologic and inflammatory responses.
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Lima, Margarida, Magdalena Leander, Marlene Santos, Ana Helena Santos, Catarina Lau, Maria Luís Queirós, Marta Gonçalves, et al. "Chemokine Receptor Expression on Normal Blood CD56+NK-Cells Elucidates Cell Partners That Comigrate during the Innate and Adaptive Immune Responses and Identifies a Transitional NK-Cell Population." Journal of Immunology Research 2015 (2015): 1–18. http://dx.doi.org/10.1155/2015/839684.
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Studies of chemokine receptors (CKR) in natural killer- (NK-) cells have already been published, but only a few gave detailed information on its differential expression on blood NK-cell subsets. We report on the expression of the inflammatory and homeostatic CKR on normal bloodCD56+lowCD16+andCD56+high CD16-/+lowNK-cells. ConventionalCD56+lowandCD56+highNK-cells present in the normal PB do express CKR for inflammatory cytokines, although with different patternsCD56+lowNK-cells are mainly CXCR1/CXCR2+and CXCR3/CCR5−/+, whereas mostlyCD56+highNK-cells are CXCR1/CXCR2−and CXCR3/CCR5+. Both NK-cell subsets have variable CXCR4 expression and are CCR4−and CCR6−. The CKR repertoire of theCD56+lowNK-cells approaches to that of neutrophils, whereas the CKR repertoire of theCD56+highNK-cells mimics that of Th1+T cells, suggesting that these cells are prepared to migrate into inflamed tissues at different phases of the immune response. In addition, we describe a subpopulation of NK-cells with intermediate levels of CD56 expression, which we namedCD56+intNK-cells. These NK-cells are CXCR3/CCR5+, they have intermediate levels of expression of CD16, CD62L, CD94, and CD122, and they are CD57−and CD158a−. In view of their phenotypic features, we hypothesize that they correspond to a transitional stage, between the well-knownCD56+highandCD56+lowNK-cells populations.
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Clemetson, Kenneth J., Jeannine M. Clemetson, Amanda E. I. Proudfoot, Christine A. Power, Marco Baggiolini, and Timothy N. C. Wells. "Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets." Blood 96, no. 13 (December 15, 2000): 4046–54. http://dx.doi.org/10.1182/blood.v96.13.4046.
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Abstract Platelets are known to contain platelet factor 4 and β-thromboglobulin, α-chemokines containing the CXC motif, but recent studies extended the range to the β-family characterized by the CC motif, including RANTES and Gro-α. There is also evidence for expression of chemokine receptors CCR4 and CXCR4 in platelets. This study shows that platelets have functional CCR1, CCR3, CCR4, and CXCR4 chemokine receptors. Polymerase chain reaction detected chemokine receptor messenger RNA in platelet RNA. CCR1, CCR3, and especially CCR4 gave strong signals; CXCR1 and CXCR4 were weakly positive. Flow cytometry with specific antibodies showed the presence of a clear signal for CXCR4 and weak signals for CCR1 and CCR3, whereas CXCR1, CXCR2, CXCR3, and CCR5 were all negative. Immunoprecipitation and Western blotting with polyclonal antibodies to cytoplasmic peptides clearly showed the presence of CCR1 and CCR4 in platelets in amounts comparable to monocytes and CCR4 transfected cells, respectively. Chemokines specific for these receptors, including monocyte chemotactic protein 1, macrophage inflammatory peptide 1α, eotaxin, RANTES, TARC, macrophage-derived chemokine, and stromal cell–derived factor 1, activate platelets to give Ca++ signals, aggregation, and release of granule contents. Platelet aggregation was dependent on release of adenosine diphosphate (ADP) and its interaction with platelet ADP receptors. Part, but not all, of the Ca++ signal was due to ADP release feeding back to its receptors. Platelet activation also involved heparan or chondroitin sulfate associated with the platelet surface and was inhibited by cleavage of these glycosaminoglycans or by heparin or low molecular weight heparin. These platelet receptors may be involved in inflammatory or allergic responses or in platelet activation in human immunodeficiency virus infection.
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Clemetson, Kenneth J., Jeannine M. Clemetson, Amanda E. I. Proudfoot, Christine A. Power, Marco Baggiolini, and Timothy N. C. Wells. "Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets." Blood 96, no. 13 (December 15, 2000): 4046–54. http://dx.doi.org/10.1182/blood.v96.13.4046.h8004046_4046_4054.
Full textAbstract:
Platelets are known to contain platelet factor 4 and β-thromboglobulin, α-chemokines containing the CXC motif, but recent studies extended the range to the β-family characterized by the CC motif, including RANTES and Gro-α. There is also evidence for expression of chemokine receptors CCR4 and CXCR4 in platelets. This study shows that platelets have functional CCR1, CCR3, CCR4, and CXCR4 chemokine receptors. Polymerase chain reaction detected chemokine receptor messenger RNA in platelet RNA. CCR1, CCR3, and especially CCR4 gave strong signals; CXCR1 and CXCR4 were weakly positive. Flow cytometry with specific antibodies showed the presence of a clear signal for CXCR4 and weak signals for CCR1 and CCR3, whereas CXCR1, CXCR2, CXCR3, and CCR5 were all negative. Immunoprecipitation and Western blotting with polyclonal antibodies to cytoplasmic peptides clearly showed the presence of CCR1 and CCR4 in platelets in amounts comparable to monocytes and CCR4 transfected cells, respectively. Chemokines specific for these receptors, including monocyte chemotactic protein 1, macrophage inflammatory peptide 1α, eotaxin, RANTES, TARC, macrophage-derived chemokine, and stromal cell–derived factor 1, activate platelets to give Ca++ signals, aggregation, and release of granule contents. Platelet aggregation was dependent on release of adenosine diphosphate (ADP) and its interaction with platelet ADP receptors. Part, but not all, of the Ca++ signal was due to ADP release feeding back to its receptors. Platelet activation also involved heparan or chondroitin sulfate associated with the platelet surface and was inhibited by cleavage of these glycosaminoglycans or by heparin or low molecular weight heparin. These platelet receptors may be involved in inflammatory or allergic responses or in platelet activation in human immunodeficiency virus infection.
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Wei, Yanzhao, Xiaohan Zheng, Ting Huang, Yuanji Zhong, Shengtong Sun, Xufang Wei, Qibing Liu, Tan Wang, and Zhenqiang Zhao. "Human embryonic stem cells secrete macrophage migration inhibitory factor: A novel finding." PLOS ONE 18, no. 8 (August 24, 2023): e0288281. http://dx.doi.org/10.1371/journal.pone.0288281.
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Macrophage migration inhibitory factor (MIF) is expressed in a variety of cells and participates in important biological mechanisms. However, few studies have reported whether MIF is expressed in human Embryonic stem cells (ESCs) and its effect on human ESCs. Two human ESCs cell lines, H1 and H9 were used. The expression of MIF and its receptors CD74, CD44, CXCR2, CXCR4 and CXCR7 were detected by an immunofluorescence assay, RT-qPCR and western blotting, respectively. The autocrine level of MIF was measured via enzyme-linked immunosorbent assay. The interaction between MIF and its main receptor was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. Finally, the effect of MIF on the proliferation and survival of human ESCs was preliminarily explored by incubating cells with exogenous MIF, MIF competitive ligand CXCL12 and MIF classic inhibitor ISO-1. We reported that MIF was highly expressed in H1 and H9 human ESCs. MIF was positively expressed in the cytoplasm, cell membrane and culture medium. Several surprising results emerge. The autosecreted concentration of MIF was 22 ng/mL, which was significantly higher than 2 ng/mL-6 ng/mL in normal human serum, and this was independent of cell culture time and cell number. Human ESCs mainly expressed the MIF receptors CXCR2 and CXCR7 rather than the classical receptor CD74. The protein receptor that interacts with MIF on human embryonic stem cells is CXCR7, and no evidence of interaction with CXCR2 was found. We found no evidence that MIF supports the proliferation and survival of human embryonic stem cells. In conclusion, we first found that MIF was highly expressed in human ESCs and at the same time highly expressed in associated receptors, suggesting that MIF mainly acts in an autocrine form in human ESCs.
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Wenzl, Kerstin, Katharina Troppan, Alexander JA Deutsch, Werner Linkesch, Peter Neumeister, and Christine Beham-Schmid. "Distinct Chemokine Receptor Profile In Chronic Lymphocytic Leukaemia and Richter Transformed Diffuse Large B Cell Lymphomas Compared To Germinal Center B Cells and De Novo Diffuse Large B Cell Lymphomas." Blood 122, no. 21 (November 15, 2013): 4852. http://dx.doi.org/10.1182/blood.v122.21.4852.4852.
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Abstract Chemokine receptors are G-protein-coupled cell surface receptors, which dissociate upon activation by their ligands and cause downstream signaling. Recently, several studies have revealed the crucial contribution of chemokine receptors and their ligands in normal B-cell differentiation and development of hematopoietic malignancies. The Richter syndrome (RS) represents the clinico-pathologic transformation of chronic lymphocytic leukaemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Due to the lack of knowledge on the chemokine receptors in RS, we aimed to investigate their expression profile in Richter syndrome patients. Therefore, we investigated the mRNA expression levels of 18 known chemokine receptors (CCR1-CCR9, CXCR1-CXCR7, XCR1, CX3CR1) by using semi-quantitative real time PCR on seven samples of paired (CLL and transformed DLBCL) RS samples, and six samples of de novo DLBCL, additionally four CLL samples –all of them transformed into DLBCL-, and eight transformed DLBCL samples –all of them originated from CLL- were included. Four samples of peripheral B cells and four samples of germinal center B cells (GCB) served as non-neoplastic controls. 11 out of 18 chemokine receptors were differentially expressed in CLL (RL) and transformed DLBCL originated from CLL (RH) compared to GCBs. RL exhibited an at least 15-fold higher expression of CCR2, CCR4, CCR7, CXCR3, and XCR1, as well as a de novo expression of CCR3, CCR8, CXCR1, CXCR2, and CX3CR1 compared to GCB. Additionally to these chemokine receptors, CCR1 also showed significant higher expression levels comparing GCB and RH samples. Only one chemokine receptor was found to be differentially expressed in our seven paired RS samples: CCR6 showed a trend of up-regulation in CLL components. Interestingly, the transformed DLBCL originated from CLL were characterized by a significant up-regulation of six chemokine receptors (CCR3, CCR7, CXCR1, CXCR3, CXCR4, and CX3CR1) and a down-regulation of CCR5 compared to DLBCL. Our data indicate that the chemokine receptor expression profile of CLL and transformed DLBCL, originated from CLL samples, differs substantially from those of non neoplastic germinal center B cells and de novo DLBCL, suggesting other cellular origin and an impact on more aggressive clinical course of Richter syndrome patients. Hence, these multiple deregulated CC and CXC receptor might serve as useful prognostic tool to separate high malignant Richter syndrome from de novo DLBCL. Disclosures: No relevant conflicts of interest to declare.
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Tarnowski, Maciej, Rui Liu, Joanna Tarnowska, Janina Ratajczak, Robert Mitchell, Mariusz Z. Ratajczak, and Magdalena Kucia. "Novel Evidence That the Small Chemokine Macrophage Migration Inhibitory Factor (MIF) Is Highly Secreted by Human Rhabdomyosarcomas, Activates Both SDF-1–binding Receptors, CXCR4 and CXCR7, and Unexpectedly Inhibits Recruitment of Stromal Cells to the Growing Tumor." Blood 116, no. 21 (November 19, 2010): 3849. http://dx.doi.org/10.1182/blood.v116.21.3849.3849.
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Abstract Abstract 3849 Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of adolescents and children and frequently infiltrates the bone marrow (BM) to the degree that it mimics acute lymphoblastic leukemia. Here we show that human RMS cells highly express and secrete the small chemokine, macrophage migration inhibitory factor (MIF). MIF overexpression has been observed in several tumors and is implicated in oncogenic transformation and tumor progression. MIF activates CXCR2 and CD74 receptors, and surprisingly, as recently reported, may also bind to the stromal-derived factor-1 (SDF-1)–binding receptor CXCR4 (Nat Med 2007;13:587). Here we report that RMS-secreted MIF i) induces phosphorylation of MAPKp42/44 and AKT, ii) stimulates RMS cell adhesion, and iii) enhances tumor vascularization. Furthermore, since RMS cells employed in our studies do not express CXCR2 and CD74 receptors, the biological effects of MIF on RMS cells depend on its interaction with CXCR4. Moreover, as we report here for the first time, receptor internalization/binding studies reveal that MIF may also engage another SDF-1–binding receptor (CXCR7) as well. Since bone marrow fibroblasts highly express the MIF-binding receptor CXCR2, we became interested in the potential role of the MIF-mediated interaction between RMS and stromal cells and, to our surprise, observed that RMS-secreted MIF decreases recruitment of stromal fibroblasts to expanding sarcomas. In support of this finding, downregulation of MIF in RMS cells inoculated into immunodeficient mice lead to formation of larger tumors that displayed higher stromal-cell support. Based on these observations, we postulate that MIF is an important autocrine/paracrine factor that stimulates both CXCR4 and CXCR7 receptors to enhance the adhesiveness of RMS cells. We also envision that MIF in those situations when it is locally secreted by a growing tumor, may desensitize CXCR4 and CXCR7 receptors expressed on the tumor cells and thus prevents their responsiveness to SDF-1 secreted at potential future sites of metastasis and thereby prevents egress of cancer cells into the circulation. On the other hand, despite its obvious pro-angiopoietic effects, MIF inhibits recruitment of stromal cells to the growing tumor. This MIF-mediated impaired recruitment of stromal elements significantly slows down as evidenced by our in vivo xenograft studies tumor growth/expansion. Based on this, we suggest that therapeutic inhibition of MIF in expanding solid tumors may accelerate both metastasis and tumor growth. Thus, the potential application of MIF inhibitors for treatment of MIF-secreting tumors should be reconsidered. Disclosures: No relevant conflicts of interest to declare.
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Ngo, Hai, Evdoxia Hatjiharissi, Xavier Leleu, Judith Runnels, Anne-Sophie Moreau, Xiaoying Jia, Garrett O’Sullivan, et al. "The CXCR4/SDF-1 Axis Regulates Migration and Adhesion in Waldenstrom Macroglobulinemia." Blood 108, no. 11 (November 1, 2006): 2418. http://dx.doi.org/10.1182/blood.v108.11.2418.2418.
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Abstract Background: Waldenstrom Macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow (BM), and lymphadenopathy in 20% of the patients, implying continuous trafficking of WM cells into and out of the BM and lymph nodes. The normal process of B-cell homing is regulated by cytokines, chemokines, and adhesion molecules. One of the most extensively studied chemokines in migration is stromal derived factor SDF-1 and its receptor CXCR4. Here we study the role of chemokine receptors, and the SDF-1/CXCR4 axis on migration and adhesion in WM. Methods: Flow cytometry for CXC and CC chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CCR2, CCR4, CCR5, CCR6 and CCR7), and adhesion molecules (VLA-4 and LFA-1) on WM cell lines (BCWM.1 and WM-WSU) and patient samples was performed. Migration was determined using the transwell migration assay (Costar, NY). Cells were placed in the upper chambers of the migration assay with 1% FCS medium in the presence of serial concentrations of SDF-1 in the lower chambers. After 4 hours of incubation, cells that migrated to the lower chambers were counted. Similarly, adhesion was determined using an adhesion assay (EMD Biosciences, San Diego, CA) with 96-well plated coated with fibronectin. Immunoblotting for proteins downstream of CXCR4 was performed. The CXCR4 inhibitor AMD3100 (10–100uM, Sigma, MO) and Gi protein inhibitor pertussis toxin PTX (10–200ng/ml, Sigma, MO) were used to inhibit CXCR4 signaling. Results: The following chemokine receptors were expressed on patient CD19+WM cells with over 30% expression: CXCR1 (mean 60%), CXCR2 (mean 47%), CXCR4 (mean 47%), CXCR5 (mean 69%), CCR4 (mean 54%) and CCR6 (mean 61%). Similar expression was observed on WM cell lines. We next determined the effect of SDF-1 on migration and signaling pathways in WM. SDF-1 (10–100nM) induced migration in a bell-shaped curve with 30nM inducing maximum migration (110% compared to control). SDF-1 30nM induced a rapid activation of signaling pathways downstream of CXCR4 including pERK1/2, pAKT, and pPKC at 1 min, with maximum activation at 5min. The CXCR4 inhibitor AMD3100 inhibited migration of BCWM.1 in the presence of 30nM SDF-1, with AMD3100 10uM inhibiting migration at 59% of control, and 20 to 50uM leading to a plateau in inhibition of migration at 54% of control. AMD3100 inhibited pERK and pPKC activation, downstream of CXCR4 in a dose-dependent fashion. Similar results were observed using PTX, with inhibition of migration of WM cells at 50% compared to control. To determine the role of SDF-1 on adhesion, we first demonstrated that WM cells from patients and cell lines expressed high levels of surface VLA-4 expression (mean 95% surface expression). WM cells had an increase in adhesion to fibronectin (VLA-4 ligand) compared to BSA control. AMD3100 10uM inhibited adhesion to fibronectin (63 % of control), indicating that the SDF-1/CXCR4 axis regulates adhesion. Conclusion: CXCR4 is highly expressed on WM cells and regulates migration and adhesion, indicating a potential role in regulating WM trafficking into the BM and lymph nodes. These studies provide the preclinical framework to study CXCR4 inhibitors in the regulation of homing and adhesion in WM.
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Cummings, C. James, Thomas R. Martin, Charles W. Frevert, Joanne M. Quan, Venus A. Wong, Steven M. Mongovin, Tonja R. Hagen, Kenneth P. Steinberg, and Richard B. Goodman. "Expression and Function of the Chemokine Receptors CXCR1 and CXCR2 in Sepsis." Journal of Immunology 162, no. 4 (February 15, 1999): 2341–46. http://dx.doi.org/10.4049/jimmunol.162.4.2341.
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Abstract Neutrophils (polymorphonuclear neutrophils; PMN) and a redundant system of chemotactic cytokines (chemokines) have been implicated in the pathogenesis of the acute respiratory distress syndrome in patients with sepsis. PMN express two cell surface receptors for the CXC chemokines, CXCR1 and CXCR2. We investigated the expression and function of these receptors in patients with severe sepsis. Compared with normal donors, CXCR2 surface expression was down-regulated by 50% on PMN from septic patients (p < 0.005), while CXCR1 expression persisted. In vitro migratory responses to the CXCR1 ligand, IL-8, were similar in PMN from septic patients and normal donors. By contrast, the migratory response to the CXCR2 ligands, epithelial cell-derived neutrophil activator (ENA-78) and the growth-related oncogene proteins, was markedly suppressed in PMN from septic patients (p < 0.05). Ab specific for CXCR1 blocked in vitro migration of PMN from septic patients to IL-8 (p < 0.05), but not to FMLP. Thus, functionally significant down-regulation of CXCR2 occurs on PMN in septic patients. We conclude that in a complex milieu of multiple CXC chemokines, CXCR1 functions as the single dominant CXC chemokine receptor in patients with sepsis. These observations offer a potential strategy for attenuating adverse inflammation in sepsis while preserving host defenses mediated by bacteria-derived peptides such as FMLP.
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Fan, Guo-Huang, Lynne A. Lapierre, James R. Goldenring, Jiqing Sai, and Ann Richmond. "Rab11-Family Interacting Protein 2 and Myosin Vb Are Required for CXCR2 Recycling and Receptor-mediated Chemotaxis." Molecular Biology of the Cell 15, no. 5 (May 2004): 2456–69. http://dx.doi.org/10.1091/mbc.e03-09-0706.
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Agonist-stimulated internalization followed by recycling to the cell membrane play an important role in fine-tuning the activity of chemokine receptors. Because the recycling of chemokine receptors is critical for the reestablishment of the cellular responsiveness to ligand, it is crucial to understand the mechanisms underlying the receptor recycling and resensitization. In the present study, we have demonstrated that the chemokine receptor CXCR2 associated with myosin Vb and Rab11-family interacting protein 2 (FIP2) in a ligand-dependent manner. Truncation of the C-terminal domain of the receptor did not affect the association, suggesting that the interactions occur upstream of the C terminus of CXCR2. After ligand stimulation, the internalized CXCR2 colocalized with myosin Vb and Rab11-FIP2 in Rab11a-positive vesicles. The colocalization lasted for ∼2 h, and little colocalization was observed after 4 h of ligand stimulation. CXCR2 also colocalized with myosin Vb tail or Rab11-FIP2 (129–512), the N-terminal–truncated mutants of myosin Vb and Rab11-FIP2, respectively, but in a highly condensed manner. Expression of the enhanced green fluorescent protein-tagged myosin Vb tail significantly retarded the recycling and resensitization of CXCR2. CXCR2 recycling was also reduced by the expression Rab11-FIP2 (129–512). Moreover, expression of the myosin Vb tail reduced CXCR2- and CXCR4-mediated chemotaxis. These data indicate that Rab11-FIP2 and myosin Vb regulate CXCR2 recycling and receptor-mediated chemotaxis and that passage of internalized CXCR2 through Rab11a-positive recycling system is critical for physiological response to a chemokine.
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Ye, Shaojing, Fei Ma, Dlovan F. D. Mahmood, Katherine L. Meyer-Siegler, Raymond E. Menard, David E. Hunt, Lin Leng, Richard Bucala, and Pedro L. Vera. "Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain." PLOS ONE 16, no. 8 (August 23, 2021): e0255975. http://dx.doi.org/10.1371/journal.pone.0255975.
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Background Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo. Methodology/Principal findings We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary human urothelial cells) and on PAR4-induced bladder hyperalgesia in vivo (mice). In mice, PAR4 induced HMGB1 release and bladder hyperalgesia through activation of intravesical MIF receptors, CD74 and CXCR4. CXCR2 was not involved in these effects. In primary urothelial cells, PAR4-induced HMGB1 release through activation of CD74 receptors. Micturition parameters in mice were not changed by any of the treatments. Conclusions/Significance Urothelial MIF receptors CD74 and CXCR4 mediate bladder pain through release of urothelial HMGB1. This mechanism may set up persistent pain loops in the bladder and warrants further investigation. Urothelial CD74 and CXCR4 may provide novel targets for interrupting bladder pain.
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Horuk, R., A. W. Martin, Z. Wang, L. Schweitzer, A. Gerassimides, H. Guo, Z. Lu, et al. "Expression of chemokine receptors by subsets of neurons in the central nervous system." Journal of Immunology 158, no. 6 (March 15, 1997): 2882–90. http://dx.doi.org/10.4049/jimmunol.158.6.2882.
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Abstract IL-8 is expressed by activated and neoplastic astrocytes and enhances the survival of hippocampal neurons in vitro. Since mRNA encoding chemokine receptors have been demonstrated in brain, the expression of chemokine receptors by specific cell types in anatomic regions of the central nervous system (CNS) was investigated. Archival tissues from various regions of the CNS were stained with specific mAbs to the Duffy Ag/receptor for chemokines, a promiscuous receptor that binds selected chemokines; the specific receptor for IL-8 (CXCR1); and the receptor (CXCR2) shared by IL-8 and melanoma growth stimulatory activity. The Duffy Ag/receptor for chemokines was expressed exclusively by Purkinje cells in the cerebellum. Chemokine binding and radioligand cross-linking confirmed the presence of a high affinity, promiscuous chemokine receptor in the cerebellum. Although CXCR1 was not expressed in the CNS, CXCR2 was expressed at high levels by subsets of projection neurons in diverse regions of the brain and spinal cord, including the hippocampus, dentate nucleus, pontine nuclei, locus coeruleus, and paraventricular nucleus, and in the anterior horn, interomediolateral cell column, and Clarke's column of the spinal cord. Fibers that express CXCR2 included those in the superior cerebellar peduncle and the substantia gelatinosa. Immunohistochemical analysis of the involved brain tissues from patients with Alzheimer's disease revealed expression of CXCR2 in the neuritic portion of plaques surrounding deposits of amyloid. These data suggest that chemokines may play a role in reactive processes in normal neuronal function and neurodegenerative disorders.
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Smithson, Alex, Maria Rosa Sarrias, Juanjo Barcelo, Belen Suarez, Juan Pablo Horcajada, Sara Maria Soto, Alex Soriano, et al. "Expression of Interleukin-8 Receptors (CXCR1 and CXCR2) in Premenopausal Women with Recurrent Urinary Tract Infections." Clinical Diagnostic Laboratory Immunology 12, no. 12 (December 2005): 1358–63. http://dx.doi.org/10.1128/cdli.12.12.1358-1363.2005.
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ABSTRACT The migration of neutrophils through infected tissues is mediated by the CXC chemokines and its receptors (CXCR1 and CXCR2). It has been proposed that a CXCR1 deficiency could confer susceptibility to acute pyelonephritis in children. The objective of the study is to assess the surface expression of CXCR1 and CXCR2 and the existence of polymorphisms in the CXCR1 gene in premenopausal women with recurrent urinary tract infections. The study included 20 premenopausal women with recurrent urinary infections, with normal urinary tracts, and without diseases potentially associated with relapsing urinary infections and 30 controls without previous urinary infections. The levels of CXCR1 and CXCR2 expression on neutrophils were measured and analyzed by flow cytometry by measuring the mean fluorescence intensity (MFI) channel. The promoter and coding regions of the CXCR1 gene were analyzed for the presence of polymorphisms by a sequence-based typing method. Patients with recurrent urinary tract infections exhibited median levels of CXCR1 expression, determined from MFI values, similar to those of the controls. The analysis of CXCR2 showed that patients with recurrent urinary infections had lower median levels of expression, determined from the MFI values, than the controls (P = 0.002, Mann-Whitney U test). No polymorphisms were detected at the promoter or at the exon 1 region of the CXCR1 gene either in the patients or in the controls. Polymorphisms were detected at the exon 2 of CXCR1, but their frequencies did not differ between patients and controls. We have found a low level of CXCR2 expression in patients with recurrent urinary tract infections. These results suggest that a low level of CXCR2 expression may increase the susceptibilities of premenopausal women to urinary tract infections.
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Berg, Christian, Michael J. Wedemeyer, Motiejus Melynis, Roman R. Schlimgen, Lasse H. Hansen, Jon Våbenø, Francis C. Peterson, Brian F. Volkman, Mette M. Rosenkilde, and Hans R. Lüttichau. "The non-ELR CXC chemokine encoded by human cytomegalovirus UL146 genotype 5 contains a C-terminal β-hairpin and induces neutrophil migration as a selective CXCR2 agonist." PLOS Pathogens 18, no. 3 (March 10, 2022): e1010355. http://dx.doi.org/10.1371/journal.ppat.1010355.
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Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised patients. The UL146 gene exists as 14 diverse genotypes among clinical isolates, which encode 14 different CXC chemokines. One genotype (vCXCL1GT1) is a known agonist for CXCR1 and CXCR2, while two others (vCXCL1GT5 and vCXCL1GT6) lack the ELR motif considered crucial for CXCR1 and CXCR2 binding, thus suggesting another receptor targeting profile. To determine the receptor target for vCXCL1GT5, the chemokine was probed in a G protein signaling assay on all 18 classical human chemokine receptors, where CXCR2 was the only receptor being activated. In addition, vCXCL1GT5 recruited β-arrestin in a BRET-based assay and induced migration in a chemotaxis assay through CXCR2, but not CXCR1. In contrast, vCXCL1GT1 stimulated G protein signaling, recruited β-arrestin and induced migration through both CXCR1 and CXCR2. Both vCXCL1GT1 and vCXCL1GT5 induced equally potent and efficacious migration of neutrophils, and ELR vCXCL1GT4 and non-ELR vCXCL1GT6 activated only CXCR2. In contrast to most human chemokines, the 14 UL146 genotypes have remarkably long C-termini. Comparative modeling using Rosetta showed that each genotype could adopt the classic chemokine core structure, and predicted that the extended C-terminal tail of several genotypes (including vCXCL1GT1, vCXCL1GT4, vCXCL1GT5, and vCXCL1GT6) forms a novel β-hairpin not found in human chemokines. Secondary NMR shift and TALOS+ analysis of vCXCL1GT1 supported the existence of two stable β-strands. C-terminal deletion of vCXCL1GT1 resulted in a non-functional protein and in a shift to solvent exposure for tryptophan residues likely due to destabilization of the chemokine fold. The results demonstrate that non-ELR chemokines can activate CXCR2 and suggest that the UL146 chemokines have unique C-terminal structures that stabilize the chemokine fold. Increased knowledge of the structure and interaction partners of the chemokine variants encoded by UL146 is key to understanding why circulating HCMV strains sustain 14 stable genotypes.
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Vacchini, Alessandro, Anneleen Mortier, Paul Proost, Massimo Locati, Mieke Metzemaekers, and Elena Borroni. "Differential Effects of Posttranslational Modifications of CXCL8/Interleukin-8 on CXCR1 and CXCR2 Internalization and Signaling Properties." International Journal of Molecular Sciences 19, no. 12 (November 27, 2018): 3768. http://dx.doi.org/10.3390/ijms19123768.
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CXCL8 or interleukin (IL)-8 directs neutrophil migration and activation through interaction with CXCR1 and CXCR2 that belong to the family of G protein-coupled receptors (GPCRs). Naturally occurring posttranslational modifications of the NH2-terminal region of CXCL8 affect its biological activities, but the underlying molecular mechanisms are only partially understood. Here, we studied the implications of site-specific citrullination and truncation for the signaling potency of CXCL8. Native CXCL8(1-77), citrullinated [Cit5]CXCL8(1-77) and the major natural isoform CXCL8(6-77) were chemically synthesized and tested in internalization assays using human neutrophils. Citrullinated and truncated isoforms showed a moderately enhanced capacity to induce internalization of CXCR1 and CXCR2. Moreover, CXCL8-mediated activation of Gαi-dependent signaling through CXCR1 and CXCR2 was increased upon modification to [Cit5]CXCL8(1-77) or CXCL8(6-77). All CXCL8 variants promoted recruitment of β-arrestins 1 and 2 to CXCR1 and CXCR2. Compared to CXCL8(1-77), CXCL8(6-77) showed an enhanced potency to recruit β-arrestin 2 to both receptors, while for [Cit5]CXCL8(1-77) only the capacity to induce β-arrestin 2 recruitment to CXCR2 was increased. Both modifications had no biasing effect, i.e., did not alter the preference of CXCL8 to activate either Gαi-protein or β-arrestin-dependent signaling through its receptors. Our results support the concept that specific chemokine activities are fine-tuned by posttranslational modifications.
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Khandaker, Masud H., Luoling Xu, Rahbar Rahimpour, Gordon Mitchell, Mark E. DeVries, J. Geoffrey Pickering, Sharwan K. Singhal, Ross D. Feldman, and David J. Kelvin. "CXCR1 and CXCR2 Are Rapidly Down-Modulated by Bacterial Endotoxin Through a Unique Agonist-Independent, Tyrosine Kinase-Dependent Mechanism." Journal of Immunology 161, no. 4 (August 15, 1998): 1930–38. http://dx.doi.org/10.4049/jimmunol.161.4.1930.
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Abstract The expression of the seven-transmembrane domain chemokine receptors CXCR1 and CXCR2 modulates neutrophil responsiveness to the chemoattractant IL-8 and a number of closely related CXC chemokines. In the present study, we investigated the mechanism by which bacterial LPS induces the down-modulation of IL-8 responsiveness and CXCR1 and CXCR2 expression on human neutrophils. Treating neutrophils with LPS reduced IL-8R expression to 55 ± 5% of the control within 30 min and to 23 ± 2% within 1 h of stimulation. Furthermore, this down-modulation could not be attributed to increased concentrations of IL-8, TNF-α, or IL-1β, since ELISA studies indicated that LPS-stimulated neutrophils did not release detectable amounts of these proteins before 2 h poststimulation. The tyrosine kinase (TK) inhibitors genistein and herbimycin A attenuated the LPS-mediated down-modulation of CXCR1 and CXCR2, indicating that the activation of a TK is required for LPS to mediate its effect. The effect of LPS on receptor expression paralleled the hyperphosphorylation of the protein TK p72syk. Although IL-8 induced a comparable down-modulation of CXCR1 and CXCR2, TK inhibitors did not attenuate this effect. These studies provide the first evidence of an agonist-independent, TK-dependent pathway of chemokine receptor regulation by endotoxin.
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Urbantat, Ruth, Anne Blank, Irina Kremenetskaia, Peter Vajkoczy, Güliz Acker, and Susan Brandenburg. "The CXCL2/IL8/CXCR2 Pathway Is Relevant for Brain Tumor Malignancy and Endothelial Cell Function." International Journal of Molecular Sciences 22, no. 5 (March 5, 2021): 2634. http://dx.doi.org/10.3390/ijms22052634.
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We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 affecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma.
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Feniger-Barish, Rotem, Dan Belkin, Alon Zaslaver, Shira Gal, Mally Dori, Maya Ran, and Adit Ben-Baruch. "GCP-2–induced internalization of IL-8 receptors: hierarchical relationships between GCP-2 and other ELR+-CXC chemokines and mechanisms regulating CXCR2 internalization and recycling." Blood 95, no. 5 (March 1, 2000): 1551–59. http://dx.doi.org/10.1182/blood.v95.5.1551.005a36_1551_1559.
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The chemotactic potencies of ELR+-CXC chemokines during acute inflammation are regulated by their binding affinities and by their ability to activate, desensitize, and internalize their specific receptors, CXCR1 and CXCR2. To gain insight into the fine mechanisms that control acute inflammatory processes, we have focused in this study on the highly potent ELR+-CXC chemokine Granulocyte Chemotactic Protein 2 (GCP-2), and on its ability to control the cell surface expression of CXCR1 and CXCR2. Although GCP-2 has been considered an effective ligand for both CXCR1 and CXCR2, our findings demonstrated that it was a potent inducer of CXCR2 internalization only. A functional hierarchy was shown to exist between GCP-2 and 2 other ELR+-CXC chemokines, IL-8 and NAP-2, in their abilities to induce CXCR1 and CXCR2 internalization, according to the following: IL-8 > GCP-2 > NAP-2. By the use of pertussis toxin (PTx), it was demonstrated that the actual events of Gi-coupling to CXCR2 do not have a major role in the regulation of its internalization. Rather, CXCR2 internalization was shown to be negatively controlled by induction of signaling events, as indicated by the promotion of CXCR2 internalization following exposure to wortmannin, a potent inhibitor of phosphatidylinositol (PI) 3 kinases and PI4 kinases. Furthermore, our results suggest that rab11+-endosomes participate in the trafficking of CXCR2 through the endocytic pathway, to eventually allow its recycling back to the plasma membrane. To conclude, our findings shed light on the interrelationships between GCP-2 and other ELR+-CXC chemokines, and determine the mechanisms involved in the regulation of GCP-2–induced internalization and recycling of CXCR2.
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Cardona, Astrid E., Margaret E. Sasse, Liping Liu, Sandra M. Cardona, Makiko Mizutani, Carine Savarin, Taofang Hu, and Richard M. Ransohoff. "Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues." Blood 112, no. 2 (July 15, 2008): 256–63. http://dx.doi.org/10.1182/blood-2007-10-118497.
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Abstract In vitro studies have implicated chemokine receptors in consumption and clearance of specific ligands. We studied the role that various signaling chemokine receptors play during ligand homeostasis in vivo. We examined the levels of ligands in serum and CNS tissue in mice lacking chemokine receptors. Compared with receptor-sufficient controls, Cx3cr1−/− mice exhibited augmented levels of CX3CL1 both in serum and brain, and circulating levels of CXCL1 and CXCL2 were increased in Cxcr2−/− mice. CCR2-deficient mice showed significantly increased amounts of circulating CCL2 compared with wild-type mice. Cxcr3−/− mice revealed increased levels of circulating and brain CXCL10 after experimental autoimmune encephalomyelitis (EAE) induction. CCR2-deficient peripheral blood and resident peritoneal cells exhibited reduced binding capacity and biologic responses to the CCR1 ligand CCL3, suggesting that elevated levels of CCR2 ligands had down-regulated CCR1. The results indicate that signaling chemokine receptors clear chemokines from circulation and tissues. These homeostatic functions of signaling chemokine receptors need to be integrated into safety and efficacy calculations when considering therapeutic receptor blockade.
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Salim, Juan P., Rosana F. Marta, and Felisa C. Molinas. "Megakaryocyte-Active Chemokines: Dysregulation in the SDF-1a/CXCR4 Axis in Patients with Essential Thrombocythemia." Blood 106, no. 11 (November 16, 2005): 4969. http://dx.doi.org/10.1182/blood.v106.11.4969.4969.
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Abstract Chemokines belong to a large family of molecules that are implicated in the localization and production of blood cells. Some of them, such as Interleukin 8 (IL-8) and GRO-a, participate in the regulation of megakaryopoiesis, mostly by exerting an inhibitory action. Recently, the involvement of stromal derived factor 1 (SDF-1) in synergizing the stimulatory effect of thrombopoietin on megakaryopoiesis and its participation in megakaryocyte transendothelial migration has been described. The aim of the present study was the evaluation of the plasma levels of IL-8, GRO- a and SDF-1 in patients with essential thrombocythemia (ET), a myeloproliferative disorder characterized by megakaryocytic hyperproliferation with increased circulating platelet count. Besides, the corresponding chemokine receptors were assayed on platelet membrane from ET patients. A cohort of 27 patients diagnosed according to the Polycitemia Vera Study Group were enrolled in the study (mean age, 45; 21 women). Twenty-seven normal subjects matched by sex and age were taken as the control group. The Ethic Committee from IDIM A. Lanari approved the study and all patients and normal controls signed the informed consent. Plasma levels of the chemokines were measured by ELISA technique (R&D Systems) according to the manufacturer. Expression levels of IL-8 receptors (CXCR1 and CXCR2), GRO-a receptors (CXCR2) and SDF-1 receptors (CXCR4) on platelet membrane were evaluated by flow cytometry using specific MoAbs and the corresponding isotype controls (B-D Pharmingen). Flow cytometry results were expressed as relative fluorescence intensity (RFI, the relationship between the mean fluorescence intensity from the specific antibody and the isotype control). Results were expressed as median and range. Statistic analysis was carried out using Mann-Whitney Wilcoxon rank sum test and Wilcoxon signed rank test. Plasma levels of the chemokines measured in 19 ET patients were similar to that found in normal controls, IL-8 2.5, pg/ml (0.8–28.2) and 2.8 pg/ml (1.1–16.5), GRO-a, 30.0 pg/ml (7.4–463.1) and 23.9 pg/ml (9.6–148.0), SDF-1, 1895.0 pg/ml (1246.0–2719.0) and 1915.0 pg/ml (822–2424.0), respectively. The expression levels of CXCR4 receptor was found diminished in platelets from ET patients, RIF 16.94 (1.3–31.3) compared to normal controls, 27.4 (2.4–58.4); p=0.0059, n=10. However, the expression of CXCR1 and CXCR2 in platelets from ET patients was normal. In conclusion, although plasma levels of the chemoquines IL-8, GRO-a and SDF-1 were normal in these patients, the decreased level of CXCR4 on platelet membrane suggests a dysregulation in the SDF-1a/CXCR4 axis in patients with essential thrombocythemia.
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Joseph, Prem Raj B., Kirti V. Sawant, and Krishna Rajarathnam. "Heparin-bound chemokine CXCL8 monomer and dimer are impaired for CXCR1 and CXCR2 activation: implications for gradients and neutrophil trafficking." Open Biology 7, no. 11 (November 2017): 170168. http://dx.doi.org/10.1098/rsob.170168.
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Chemokine CXCL8 plays a pivotal role in host immune response by recruiting neutrophils to the infection site. CXCL8 exists as monomers and dimers, and mediates recruitment by interacting with glycosaminoglycans (GAGs) and activating CXCR1 and CXCR2 receptors. How CXCL8 monomer and dimer interactions with both receptors and GAGs mediate trafficking is poorly understood. In particular, both haptotactic (mediated by GAG-bound chemokine) and chemotactic (mediated by soluble chemokine) gradients have been implicated, and whether it is the free or the GAG-bound CXCL8 monomer and/or dimer that activates the receptor remains unknown. Using solution NMR spectroscopy, we have now characterized the binding of heparin-bound CXCL8 monomer and dimer to CXCR1 and CXCR2 receptor N-domains. Our data provide compelling evidence that heparin-bound monomers and dimers are unable to bind either of the receptors. Cellular assays also indicate that heparin-bound CXCL8 is impaired for receptor activity. Considering dimer binds GAGs with higher affinity, dimers will exist predominantly in the GAG-bound form and the monomer in the free form. We conclude that GAG interactions determine the levels of free CXCL8, and that it is the free, and not GAG-bound, CXCL8 that activates the receptors and mediates recruitment of blood neutrophils to the infected tissue.
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Desbaillets, Isabelle, Annie-Claire Diserens, Nicolas de Tribolet, Marie-France Hamou, and Erwin G. Van Meir. "Upregulation of Interleukin 8 by Oxygen-deprived Cells in Glioblastoma Suggests a Role in Leukocyte Activation, Chemotaxis, and Angiogenesis." Journal of Experimental Medicine 186, no. 8 (October 20, 1997): 1201–12. http://dx.doi.org/10.1084/jem.186.8.1201.
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Leukocyte infiltration and necrosis are two biological phenomena associated with the development of neovascularization during the malignant progression of human astrocytoma. Here, we demonstrate expression of interleukin (IL)-8, a cytokine with chemotactic and angiogenic properties, and of IL-8–binding receptors in astrocytoma. IL-8 expression is first observed in low grade astrocytoma in perivascular tumor areas expressing inflammatory cytokines. In glioblastoma, it further localizes to oxygen-deprived cells surrounding necrosis. Hypoxic/anoxic insults on glioblastoma cells in vitro using anaerobic chamber systems or within spheroids developing central necrosis induced an increase in IL-8 messenger RNA (mRNA) and protein expression. mRNA for IL-8–binding chemokine receptors CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC) were found in all astrocytoma grades by reverse transcription/PCR analysis. In situ hybridization and immunohistochemistry localized DARC expression on normal brain and tumor microvascular cells and CXCR1 and CXCR2 expression to infiltrating leukocytes. These results support a model where IL-8 expression is initiated early in astrocytoma development through induction by inflammatory stimuli and later in tumor progression increases due to reduced microenvironmental oxygen pressure. Augmented IL-8 would directly and/or indirectly promote angiogenesis by binding to DARC and by inducing leukocyte infiltration and activation by binding to CXCR1 and CXCR2.
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Govindaraju, Vasanthi, Marie-Claire Michoud, Mustafa Al-Chalabi, Pasquale Ferraro, William S. Powell, and James G. Martin. "Interleukin-8: novel roles in human airway smooth muscle cell contraction and migration." American Journal of Physiology-Cell Physiology 291, no. 5 (November 2006): C957—C965. http://dx.doi.org/10.1152/ajpcell.00451.2005.
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In patients with cystic fibrosis (CF) and asthma, elevated levels of interleukin-8 (IL-8) are found in the airways. IL-8 is a CXC chemokine that is a chemoattractant for neutrophils through CXCR1 and CXCR2 G protein-coupled receptors. We hypothesized that IL-8 acts directly on airway smooth muscle cells (ASMC) in a way that may contribute to the enhanced airway responsiveness and airway remodeling observed in CF and asthma. The aim of this study was to determine whether human ASMC (HASMC) express functional IL-8 receptors (CXCR1 and CXCR2) linked to cell contraction and migration. Experiments were conducted on cells harvested from human lung specimens. Real-time PCR and fluorescence-activated cell sorting analysis showed that HASMC expressed mRNA and protein for both CXCR1 and CXCR2. Intracellular Ca2+ concentration ([Ca2+]i) increased from 115 to 170 nM in response to IL-8 (100 nM) and decreased after inhibition of phospholipase C (PLC) with U-73122. On blocking the receptors with specific neutralizing antibodies, changes in [Ca2+]i were abrogated. IL-8 also contracted the HASMC, decreasing the length of cells by 15%, and induced a 2.5-fold increase in migration. These results indicate that HASMC constitutively express functional CXCR1 and CXCR2 that mediate IL-8-triggered Ca2+ release, contraction, and migration. These data suggest a potential role for IL-8 in causing abnormal airway structure and function in asthma and CF.
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Weisel, Katja C., Frank Bautz, Gabriele Seitz, Sedat Yildirim, Lothar Kanz, and Robert Möhle. "Modulation of CXC Chemokine Receptor Expression and Function in Human Neutrophils during Aging In Vitro Suggests a Role in Their Clearance from Circulation." Mediators of Inflammation 2009 (2009): 1–8. http://dx.doi.org/10.1155/2009/790174.
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In mice, differential regulation of CXC chemokine receptor expression in circulating polymorphonuclear neutrophils (PMNs) undergoing senescence results in homing to the bone marrow. However, the role of this compartment and of the chemokine receptor CXCR4 is still under discussion, and only scarce data exist about CXCR4 function in human PMN. In our study, we provide evidence that also in human neutrophils, expression (cell surface and mRNA), chemotactic and signaling functions of the homing-related chemokine receptor CXCR4 are upregulated during aging in vitro, independent of addition of stimulatory cytokines (TNF, IL-1, IL-8, G-CSF). In contrast, interleukin-8 receptors are downmodulated (CXCR2) or remain unchanged (CXCR1), suggesting that human PMNs undergoing senescence acquire a phenotype that impairs inflammatory extravasation and favors homing to the bone marrow or other tissues involved in sequestration. Partially retained responsiveness to interleukin-8 may be important for neutrophil function when senescence occurs after extravasation in inflamed tissues.
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Semple, Bridgette D., Thomas Kossmann, and Maria Cristina Morganti-Kossmann. "Role of Chemokines in CNS Health and Pathology: A Focus on the CCL2/CCR2 and CXCL8/CXCR2 Networks." Journal of Cerebral Blood Flow & Metabolism 30, no. 3 (November 11, 2009): 459–73. http://dx.doi.org/10.1038/jcbfm.2009.240.
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Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.
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Sobolik, Tammy, Ying-jun Su, Sam Wells, Gregory D. Ayers, Rebecca S. Cook, and Ann Richmond. "CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways." Molecular Biology of the Cell 25, no. 5 (March 2014): 566–82. http://dx.doi.org/10.1091/mbc.e13-07-0360.
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Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box–binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte–macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.
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Takahashi, Masafumi, Takatoshi Ishiko, Hidenobu Kamohara, Hideaki Hidaka, Osamu Ikeda, Michio Ogawa, and Hideo Baba. "Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1, 6-heptadiene-3,5-dione) Blocks the Chemotaxis of Neutrophils by Inhibiting Signal Transduction through IL-8 Receptors." Mediators of Inflammation 2007 (2007): 1–11. http://dx.doi.org/10.1155/2007/10767.
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We investigated the impact of curcumin on neutrophils. Chemotactic activity via human recombinant IL-8 (hrIL-8) was significantly inhibited by curcumin. Curcumin reduced calcium ion flow induced by internalization of the IL-8 receptor. We analyzed flow cytometry to evaluate the status of the IL-8 receptor after curcumin treatment. The change in the distribution of receptors intracellularly and on the cell surface suggested that curcumin may affect the receptor trafficking pathway intracellulary. Rab11 is a low molecular weight G protein associated with the CXCR recycling pathway. Following curcumin treatment, immunoprecipitation studies showed that the IL-8 receptor was associated with larger amounts of active Rab11 than that in control cells. These data suggest that curcumin induces the stacking of the Rab11 vesicle complex with CXCR1 and CXCR2 in the endocytic pathway. The mechanism for antiinflammatory response by curcumin may involve unique regulation of the Rab11 trafficking molecule in recycling of IL-8 receptors.
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Parenty, Geraldine, Shirley Appelbe, and Graeme Milligan. "CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2–DOP receptor heterodimer." Biochemical Journal 412, no. 2 (May 14, 2008): 245–56. http://dx.doi.org/10.1042/bj20071689.
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Opioid agonists have a broad range of effects on cells of the immune system, including modulation of the inflammatory response, and opioid and chemokine receptors are co-expressed by many white cells. Hetero-oligomerization of the human DOP opioid and chemokine CXCR2 receptors could be detected following their co-expression by each of co-immunoprecipitation, three different resonance energy transfer techniques and the construction of pairs of individually inactive but potentially complementary receptor G-protein α subunit fusion proteins. Although DOP receptor agonists and a CXCR2 antagonist had no inherent affinity for the alternative receptor when either receptor was expressed individually, use of cells that expressed a DOP opioid receptor construct constitutively, and in which expression of a CXCR2 receptor construct could be regulated, demonstrated that the CXCR2 antagonist enhanced the function of DOP receptor agonists only in the presence of CXCR2. This effect was observed for both enkephalin- and alkaloid-based opioid agonists, and the effective concentrations of the CXCR2 antagonist reflected CXCR2 receptor occupancy. Entirely equivalent results were obtained in cells in which the native DOP opioid receptor was expressed constitutively and in which expression of the isolated CXCR2 receptor could be induced. These results indicate that a CXCR2 receptor antagonist can enhance the function of agonists at a receptor for which it has no inherent direct affinity by acting as an allosteric regulator of a receptor that is a heterodimer partner for the CXCR2 receptor. These results have novel and important implications for the development and use of small-molecule therapeutics.
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Adekoya, Timothy O., Nikia Smith, Parag Kothari, Monique A. Dacanay, Yahui Li, and Ricardo M. Richardson. "CXCR1 Expression in MDA-PCa-2b Cell Upregulates ITM2A to Inhibit Tumor Growth." Cancers 16, no. 24 (December 11, 2024): 4138. https://doi.org/10.3390/cancers16244138.
Full textAbstract:
Background: Chemokines, along with their receptors, exert critical roles in tumor development and progression. In prostate cancer (PCa), interleukin-8 (IL-8/CXCL8) was shown to enhance angiogenesis, proliferation, and metastasis. CXCL8 activates two receptors, CXCR1 and CXCR2. While CXCR2 expression was shown to promote PCa growth and metastasis, the role of CXCR1 remains unclear. Methods: In this study, we stably expressed CXCR1 and, as control, CXCR2 in the androgen-dependent PCa cell line MDA-PCa-2b to evaluate the effect of CXCR1 in tumor development. Results: MDA-PCa-2b-CXCR1 cells showed decreased cell migration, protein kinase-B (AKT) activation, prostate-specific antigen (PSA) expression, cell proliferation, and tumor development in nude mice, relative to MDA-PCa-2b-Vec and MDA-PCa-2b-CXCR2 cells. MDA-PCa-2b-CXCR1 cells also displayed a significant transition to mesenchymal phenotypes as characterized by decreased E-cadherin expression and a corresponding increased level of N-cadherin and vimentin expression. RNA-seq and Western blot analysis revealed a significant increase in the tumor suppressor integral membrane protein 2A (ITM2A) expression in MDA-PCa-2b-CXCR1 compared to control cells. In prostate adenocarcinoma tissue, ITM2A expression was also shown to be downregulated relative to a normal prostate. Interestingly, the overexpression of ITM2A in MDA-PCa-2b cells (MDA-PCa-2b-ITM2A-GFP) inhibited tumor growth similar to that of MDA-PCa-2b-CXCR1. Conclusions: Taken together, the data suggest that CXCR1 expression in MDA-PCa-2b cells may upregulate ITM2A to abrogate tumor development.
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Piotrowska, Anna, Katarzyna Ciapała, Katarzyna Pawlik, Klaudia Kwiatkowski, Ewelina Rojewska, and Joanna Mika. "Comparison of the Effects of Chemokine Receptors CXCR2 and CXCR3 Pharmacological Modulation in Neuropathic Pain Model—In Vivo and In Vitro Study." International Journal of Molecular Sciences 22, no. 20 (October 14, 2021): 11074. http://dx.doi.org/10.3390/ijms222011074.
Full textAbstract:
Recent findings have highlighted the roles of CXC chemokine family in the mechanisms of neuropathic pain. Our studies provide evidence that single/repeated intrathecal administration of CXCR2 (NVP-CXCR2-20) and CXCR3 ((±)-NBI-74330) antagonists explicitly attenuated mechanical/thermal hypersensitivity in rats after chronic constriction injury of the sciatic nerve. After repeated administration, both antagonists showed strong analgesic activity toward thermal hypersensitivity; however, (±)-NBI-74330 was more effective at reducing mechanical hypersensitivity. Interestingly, repeated intrathecal administration of both antagonists decreased the mRNA and/or protein levels of pronociceptive interleukins (i.e., IL-1beta, IL-6, IL-18) in the spinal cord, but only (±)-NBI-74330 decreased their levels in the dorsal root ganglia after nerve injury. Furthermore, only the CXCR3 antagonist influenced the spinal mRNA levels of antinociceptive factors (i.e., IL-1RA, IL-10). Additionally, antagonists effectively reduced the mRNA levels of pronociceptive chemokines; NVP-CXCR2-20 decreased the levels of CCL2, CCL6, CCL7, and CXCL4, while (±)-NBI-74330 reduced the levels of CCL3, CCL6, CXCL4, and CXCL9. Importantly, the results obtained from the primary microglial and astroglial cell cultures clearly suggest that both antagonists can directly affect the release of these ligands, mainly in microglia. Interestingly, NVP-CXCR2-20 induced analgesic effects after intraperitoneal administration. Our research revealed important roles for CXCR2 and CXCR3 in nociceptive transmission, especially in neuropathic pain.
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Antas, Paulo, Steven Holland, and Timothy Sterling. "Abnormal spontaneous interleukin 8 receptor expression: a brief report of two cases." Revista da Sociedade Brasileira de Medicina Tropical 45, no. 1 (February 2012): 134–37. http://dx.doi.org/10.1590/s0037-86822012000100029.
Full textAbstract:
Interleukin 8 (CXCL8) is an autocrine chemokine specific for the chemoattraction and activation of granulocytes, NKT cells and T lymphocytes. Patients with tuberculosis and latent Mycobacterium tuberculosis infection were assessed for the spontaneous expression of CXCR1 (CD128) and CXCR2 on lymphocytes and monocytes. Compared with ex vivo profiles, increased spontaneous CXCR2 expression and normal CXCR1 expression were found on lymphocytes in two out of 59 individuals. Monocytes showed normal ex vivo profiles for both receptors. After stimulation with purified protein derivative, the in vitro levels of CXCL8 were below the median levels of all patients with prior tuberculosis. Spontaneous CXCR2 modulation did not cause notable variation in the in vitro levels of CXCL8.
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Murashka, D. I., A. D. Tahanovich, M. M. Kauhanka, O. V. Gotko, and V. I. Prokhorova. "On the issue of diagnostic value of determining the level of receptors and their ligands in blood in non-small cell lung cancer." Russian Clinical Laboratory Diagnostics 67, no. 5 (May 21, 2022): 277–85. http://dx.doi.org/10.51620/0869-2084-2022-67-5-277-285.
Full textAbstract:
Non-small cell lung cancer (NSCLC) occupies the first place in the structure of mortality due to oncological diseases. Late diagnosis worsens the effectiveness of its treatment. There are no informative biomarkers that allow us to judge the prevalence of the tumor process, especially in the early stages of NSCLC. To determine the level of CXCL5, CXCL8, CXCR1 and CXCR2 in the peripheral blood of patients with NSCLC to assess the possibility of their use in the diagnosis of the disease. The material was the blood of 218 patients with NSCLC, 19 patients with lung hamartoma and 42 healthy people. The concentration of CXCL5, CXCL8, and SCC in blood serum was determined by enzyme immunoassay, the CYFRA 21-1 level was determined by immunochemiluminescence analysis. The proportion of leukocytes equipped with CXCR1 and CXCR2 receptors and the fluorescence intensity of receptor complexes with antibodies (MFI) in them were measured by flow cytometry. MFI CXCR1 in granulocytes and the proportion of lymphocytes supplied CXCR2, increased in the blood already at stage I of NSCLC and showed an even more significant increase in subsequent stages. The level of these indicators was correlatively related to the stages and characteristics of NSCLC. Measuring the level of MFI CXCR1 in the blood serum makes it possible to diagnose the early stages of NSCLC with a sensitivity of 87.4% (specificity - 73.8%). Determination of the proportion of lymphocytes equipped with CXCR2 demonstrates comparable diagnostic sensitivity (87.2%) and specificity of 66.7% in the detection of stages I-II of NSCLC. MFI CXCR1 in granulocytes can also be used to differentiate stages I and II of NSCLC (diagnostic sensitivity - 75,3%, specificity - 69,6%). The sensitivity of determining for this purpose the proportion of lymphocytes equipped with CXCR2 is 75.0% with a specificity of 71.7%. In 89.7% of patients with stages III-IV NSCLC, the MFI CXCR1 in granulocytes exceeds the threshold value of 47.8 (specificity - 74.8%). Diagnostic sensitivity of determining the proportion of lymphocytes for this purpose was 90.7%.