Activation of CXCR4 by the CXC chemokine stromal cell-derived factor-1 (SDF-1) requires interaction of the amino-terminal domains of both molecules. We report that proteinases released from either mononucleated blood cells or polymorphonuclear neutrophils degranulated by inflammatory stimuli generate an SDF-1 fragment that is deleted from amino-terminal residues Lys(1)-Pro(2)-Val(3), as characterized by mass spectrometry analysis. The proteolyzed chemokine fails to induce agonistic functions and is unable to prevent the fusogenic capacity of CXCR4-tropic human immunodeficiency viruses. Furthermore, we observed that exposure of CXCR4-expressing cells to leukocyte proteinases results in the proteolysis of the extracellular amino-terminal domain of the receptor, as assessed by flow cytometry analysis and electrophoretic separation of immunoprecipitated CXCR4. Blockade of SDF-1 and CXCR4 proteolysis by the specific leukocyte elastase inhibitor, N-methoxysuccinyl-alanine-alanine-proline-valine-chloromethyl

TY - JOUR. T1 - The role of metabotropic glutamate receptor 5 on the stromal cell-derived factor-1/CXCR4 system in oral. AU - Kuribayashi, Nobuyuki. AU - Uchida, Daisuke. AU - Kinouchi, Makoto. AU - Takamaru, Natsumi. AU - Tamatani, Tetsuya. AU - Nagai, Hirokazu. AU - Miyamoto, Youji. PY - 2013/11/13. Y1 - 2013/11/13. N2 - We have demonstrated that blocking CXCR4 may be a potent anti-metastatic therapy for CXCR4-related oral cancer. However, as CXCR4 antagonists are currently in clinical use to induce the mobilization of hematopoietic stem cells, continuous administration as an inhibitor for the metastasis may lead to persistent leukocytosis. In this study, we investigated the novel therapeutic downstream target(s) of the SDF-1/CXCR4 system, using B88-SDF-1 cells, which have an autocrine SDF-1/CXCR4 system and exhibit distant metastatic potential in vivo. Microarray analysis revealed that 418 genes were upregulated in B88-SDF-1 cells. We identified a gene that is highly upregulated in B88-SDF-1 ...

The mild neuroinflammation hypothesis of schizophrenia was introduced by Bechter in 2001.It has been hypothesized that a hypofunction of glutamatergic signaling via N-methyl-n-aspartate receptors (NMDARs) and hyperactivation of dopamine D2 receptors play a role in schizophrenia. The triplet puzzle theory states that sets of triplet amino acid homologies guide two different receptors towards each other and contributes to the formation of a receptor heteromer. It is therefore proposed that putative NMDAR- C-C chemokine receptor type 2 (CCR2), NMDAR- C-X-C chemokine receptor type 4 (CXCR4) and NMDAR- Interleukin 1 receptor type II (IL1R2) heteromers can be formed in the neuronal networks in mild neuroinflammation due to demonstration of Gly-Leu-Leu (GLL), Val-Ser-Thr (VST) and/or Ser-Val-Ser (SVS) amino acid homologies between these receptor protomers. This molecular process may underlie the ability to produce symptoms of schizophrenia in mild neuroinflammation. In this state volume transmission is

CXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins, since they span the cell membrane seven times. There are currently seven known CXC chemokine receptors in mammals, named CXCR1 through CXCR7. CXCR1 and CXCR2 are closely related receptors that recognize CXC chemokines that possess an E-L-R amino acid motif immediately adjacent to their CXC motif. CXCL8 (otherwise known as interleukin-8) and CXCL6 can both bind CXCR1 in humans, while all other ELR-positive chemokines, such as CXCL1 to CXCL7 bind only CXCR2. They are both expressed on the surface of neutrophils in mammals. CXCR3 is expressed predominantly on T cells (T lymphocytes), and also on other lymphocytes [some B cells (B lymphocytes) and NK cells] and is highly induced following cell activation. There are two ...

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. Patient WHIM-09 was spontaneously cured by chromothriptic deletion of 1 copy of 164 genes, including the CXCR4WHIM allele, presumably in a single hematopoietic stem cell (HSC) that repopulated HSCs and the myeloid lineage. Testing the specific contribution of CXCR4 hemizygosity to her cure, we previously demonstrated enhanced engraftment of Cxcr4+/o HSCs after transplantation in WHIM (Cxcr4+/w) model mice, but the potency was not quantitated. We now report graded-dose competitive transplantation experiments using lethally irradiated Cxcr4+/+ recipients in which mixed BM cells containing approximately 5 Cxcr4+/o HSCs and a 100-fold excess of Cxcr4+/w HSCs achieved durable 50% Cxcr4+/o myeloid and B cell chimerism in blood and approximately 20% Cxcr4+/o HSC chimerism in BM. In Cxcr4+/o/Cxcr4+/w parabiotic mice, we ...

Among chemokine receptors, CXCR4 has been found to be most widely expressed in multiple types of tumors and has been shown to be implicated in tumor cell invasion, metastasis, as well as in survival and proliferation (2, 5). Less information is available on the occurrence and biological role of the newly discovered second receptor for the CXCR4-ligand CXCL12, i.e., CXCR7 (8, 12-14). Reportedly, human gliomas and astrocytomas produce several chemokines like CCL2/MCP-1, CXCL8/interleukin-8, CXCL10, CXCL11/I-TAC, CXCL12/stromal cell-derived factor-1, and CXCL16 (19, 26). Their corresponding receptors have been identified either on astrocytoma/glioma cells (or subsets), on tumor-infiltrating microglial cells/macrophages, on tumor endothelial cells, or on tumor-infiltrating neural stem cells (17, 27).. CXCR4 has been originally described as a major widespread receptor on glioma cells (3, 4), and its occurrence and localization were addressed in several previous studies. WHO grade 3 and 4 glial tumors ...

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. Patient WHIM-09 was spontaneously cured by chromothriptic deletion of 1 copy of 164 genes, including the CXCR4WHIM allele, presumably in a single hematopoietic stem cell (HSC) that repopulated HSCs and the myeloid lineage. Testing the specific contribution of CXCR4 hemizygosity to her cure, we previously demonstrated enhanced engraftment of Cxcr4+/o HSCs after transplantation in WHIM (Cxcr4+/w) model mice, but the potency was not quantitated. We now report graded-dose competitive transplantation experiments using lethally irradiated Cxcr4+/+ recipients in which mixed BM cells containing approximately 5 Cxcr4+/o HSCs and a 100-fold excess of Cxcr4+/w HSCs achieved durable 50% Cxcr4+/o myeloid and B cell chimerism in blood and approximately 20% Cxcr4+/o HSC chimerism in BM. In Cxcr4+/o/Cxcr4+/w parabiotic mice, we ...

Oregon Grape, a popular source of Berberine. SDF-1 binds to a receptor named CXCR-4 (short for C-X-C chemokine receptor type 4. SDF-1 is sometimes referred to as CXCL12, thats where the CXC comes from, but lets try to keep this simple).. Leukemia tumor cells express this CXCR-4 receptor either on their surface or inside the cell. They notice and respond to SDF-1. This cSFD-1/CXCR4 signaling pathway involved in the migration of leukemic cells though the body. A 2008 paper by Li et al reported that because berberine … could partly inhibit SDF-1 induced AML [acute myeloid leukemia] cells as well as LSCs [leukemic stem cells] migration…… [the authors] hypothesized that berberine could inhibit AML cells migration partly by reducing the secreting of SDF-1 …... Therefore, [they] speculated that berberine might be a potentially effective agent for prevention of leukemia. [1] This hypothesis was based in part by an earlier paper by Tavor et al that looked at the role of CXCR4 in the ...

Particular populations of stem cells in the bone marrow harbors the membrane receptor CXCR4 which is a specific receptor for chemokine stromal cell-derived factor (SDF-1). In addition, the presence of CXCR4 identifies cells showing expression of early cardiac, muscle and endothelial markers. In mice experiments it was shown that bone marrow contains pools of cells that express early cardiac lineage markers (Nkx2.5/Csx, GATA-4, and MEF2C) and the population can be mobilised by inducing the myocardial infarction. This is the first proof that postnatal bone marrow contains nonhematopoietic population of cells that express markers for cardiac differentiation [4-6]. The peak expression of cardiac markers was found at the same time as most significant increase of stem cells number was measured [12]. A Similar phenomenon seems to occur in humans in the setting of AMI [10]. The SDF-1/CXCR-4 axis seems particularly important in stem/progenitor cell homing, chemotaxis, engrafment and retention in ...

IPF is a progressive disease for which two antifibrotic drugs have recently been approved, however there is an unmet need to predict responses to antifibrotic treatment, such as pirfenidone. Recent data suggested that up-regulated expression of the C-X-C chemokine-receptor type 4 (CXCR4) is indicative of outcomes in IPF.Can quantitative, molecular imaging of pulmonary CXCR4 expression as a biomarker for disease activity predict response to the targeted treatment pirfenidone and prognosis in patients with IPF?CXCR4 expression was analyzed by immunohistochemistry of lung tissues and RT-PCR of BAL. PET-CT with the specific CXCR4 ligand, gallium-68 (68Ga)-pentixafor, was performed in 28 IPF patients (PET1) and compared with baseline clinical characteristics. In 16 patients, a follow-up scan (PET2) was obtained 6-12 weeks after initiation of treatment with pirfenidone. Patients were followed in our outpatient clinic for ≥12 months.Immunohistochemistry showed high CXCR4 staining of epithelial cells ...

The version of the article, Human Umbilical Vein Endothelial Cells Protect Against Hypoxic-Ischemic Damage in Neonatal Brain via Stromal Cell-derived Factor 1/C-X-C Chemokine Receptor Type 4 by Wu et al that published online ahead-of-print on February 28, 2013, and appears in the May issue (Stroke. 2013;44:1402-1409) contained an error in Ying-Chao Changs affiliation. The correct affiliation is Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. The authors regret the error.. This correction has been made to the online version of the article, which is available at http://stroke.ahajournals.org/content/44/5/1402.. ...

Looking for online definition of CXCR1 in the Medical Dictionary? CXCR1 explanation free. What is CXCR1? Meaning of CXCR1 medical term. What does CXCR1 mean?

The role of SDF-1/CXCR4 in the vasculogenesis and remodeling of cerebral arteriovenous malformation Lingyan Wang,1 Shaolei Guo,2 Nu Zhang,2 Yuqian Tao,3 Heng Zhang,1 Tiewei Qi,2 Feng Liang,2 Zhengsong Huang2 1Department of Neurosurgery ICU, 2Department of Neurosurgery, 3Department of Neurology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China Background: Cerebral arteriovenous malformation (AVM) involves the vasculogenesis of cerebral blood vessels and can cause severe intracranial hemorrhage. Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, are believed to exert multiple physiological functions including angiogenesis. Thus, we investigated the role of SDF-1/CXCR4 in the vasculogenesis of cerebral AVM.Methods: Brain AVM lesions from surgical resections were analyzed for the expression of SDF-1, CXCR4, VEGF-A, and HIF-1 by using immunohistochemical staining. Flow cytometry was used to quantify the level of circulating endothelial

Hypoxia, a hallmark of malignant tumors, often correlates with increasing tumor aggressiveness and poor treatment outcomes. Due to a lack of vasculature, effective drug delivery to hypoxic tumor regions remains challenging. Signaling through the chemokine SDF-1alpha and its receptor CXCR4 plays a critical role in the homing of stem cells to ischemia for potential use as drug-delivery vehicles. To harness this mechanism for targeting tumor hypoxia, we developed polymeric nanoparticle-induced CXCR4-overexpressing human adipose-derived stem cells (hADSCs). Using glioblastoma multiforme (GBM) as a model tumor, we evaluated the ability of CXCR4-overexpressing hADSCs to target tumor hypoxia in vitro using a 2D migration assay and a 3D collagen hydrogel model. Compared to untransfected hADSCs, CXCR4-overexpressing hADSCs showed enhanced migration in response to hypoxia and penetrated the hypoxic core within tumor spheres. When injected in the contralateral brain in a mouse intracranial GBM xenograft, ...

Everolimus (RAD001, Afinitor) is an mTOR inhibitor FDA-approved for the treatment of patients with advanced clear cell renal cancer (RCC) after failure of treatment with sunitinib or sorafenib, or both drugs. It targets the mammalian target of rapamycin (mTOR) complex inhibiting a serine/threonine kinase regulating PI3K/AKT signaling pathway. Previous evidences demonstrated that the activation of the chemokine receptor CXCR4 involved the mTOR pathway and that CXCR4 was overexpressed in RCC. Recently, also the deorphanized chemokine receptor CXCR7 was described in RCC and defined as an independent prognostic factor. Nevertheless, little is known about the CXCR4-CXCL12-CXCR7-induced signalling. Aim of the study was to investigate if the CXCL12/CXCR4/CXCR7 complex could transduce the signal through mTOR identifying new therapeutic targets. In human renal cancer cells (RXF393, A498) treatment with CXCL12, the CXCR4 and CXCR7 ligand, induced mTOR pathway, as demonstrated through p70S6K and eukaryotic ...

The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738. In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10

CXCL12 [ENSP00000379140]. Pre-B cell growth-stimulating factor; Chemoattractant active on T-lymphocytes, monocytes, but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. Also binds to atypical chemokine receptor ACKR3, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. SDF-1-beta(3-72) and SDF-1- alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3- 67) and thus to preserve activity on local sites. Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and ACKR3, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of ...

In general terms, the systemic inflammatory response is an entirely normal host response to remove pathogens; however, if excessive, it may lead to damage to host tissues of lung and liver systems, multiple organ dysfunction syndrome, and a high mortality rate (3). Because it is well established that chemokines play a key role in controlling leukocyte recruitment and activation, many researchers have investigated the role of chemokine receptors during sepsis (17). Most of these studies have focused on CXC chemokine receptors, especially CXCR1 and CXCR2. Mice deficient in CXCR2 or treated with CXCR2-specific antibodies are protected from developing sepsis (14). Blockade of CXCR2 by antileukinate, a hexapeptide inhibitor of CXC-chemokine receptor, significantly attenuates lung damage (9). Moreover, pepducins derived from intracellular loops of CXCR1 and CXCR2 reverse the lethal consequence of sepsis, including disseminated intravascular coagulation and multiple organ failure in mice (8).. Recent ...

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR− neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity. ...

Chemoattractant active on T-lymphocytes and monocytes but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Also binds to atypical chemokine receptor ACKR3, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. Binds to the allosteric site (site 2) of integrins and activates integrins ITGAV:ITGB3, ITGA4:ITGB1 and ITGA5:ITGB1 in a CXCR4-independent manner (PubMed:29301984). Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and ACKR3, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for ...

Purpose: : Stromal cell-derived factor-1 (SDF-1) was reported to have significant functions in retinal angiogenesis and the recruitment of hematopoietic stem cell-derived cells. We here assessed the contribution of the SDF-1/CXCR4 axis to the neovascular sprouting from the retinal vasculature in ex vivo and in vivo models. Methods: : (ex vivo) The retinas isolated from 7- to 8-week-old C57BL6/J mice were cultured for 4 days with 25 ng/ml vascular endothelial growth factor (VEGF), with or without anti-SDF-1 antibody or CXCR4 inhibitor (AMD 3100). The neovascular sprouts (PECAM-positive and collagen type IV negative sprouts) were quantified. For the time-sequential imaging, the retinas of Tie2-GFP transgenic mice were treated with VEGF for 4 days, followed by AMD 3100 treatment and the image acquisition. (in vivo) AMD3100 was intraperitoneally injected into C57BL6/J mice on postnatal day 3 (P3), and the eyes were isolated and fixed on P4. After the staining with anti-PECAM antibodies, the radius ...

Chemokine receptors play a role in leukocyte recruitment, activation, and maintaining effector functions and regulate adaptive immune response and angiogenesis. The study aimed at flow cytometric analysis of T cell subsets with selected surface chemokine receptors (CCR4, CCR5, CCR7, CXCR3, and CXCR4) or receptor combination in peripheral blood of children with chronic kidney disease (CKD) on hemodialysis (HD). The percentage of T lymphocytes with CD8 and combined CD28,CCR7 expression was higher in HD children. The percentage of T lymphocytes expressing CCR7, CD28,CCR7, and CXCR4,CD8 was increased in children on conservative treatment. Total number (tn) of CXCR4+ cells was reduced in children on hemodialysis. The tn of T CXCR3+ cells was lower in children on conservative treatment. During HD the percentage of T CD4+ cells was higher and of T CXCR3+ lymphocytes was lower after HD session as compared to 15 min of session duration. During HD tn of T cells with expression of CCR4, CCR5, CCR7, CXCR3,

Since the original descriptions of the role of stromal cell-derived factor (SDF)-1 in recruiting bone marrow derived stem cells to the sites of vascular1 and myocardial injury,2 there has been increasing evidence of the broader importance of the SDF-1:CXCR4 axis in regulating myocardial repair following ischemic injury.2-6 In this issue of Circulation Research, Tang et al investigate the role of the SDF-1:CXCR4 axis in the recruitment of exogenously derived cardiac stem cells.7 They further investigate how cardiac stem cell exposure to hypoxia before their intravenous administration alters cardiac stem cell engraftment and subsequent effects on myocardial repair.. Cardiac stem cells were derived from cardiosphere cultures and were defined by as CLK (cardiosphere-derived c-Kit+ Lin−) cells. The cells were shown to have evidence of cardiac potential through the expression of green fluorescent protein under control of the Nkx2.5 promoter. The cells were administered intravenously 1 hour following ...

Novel Stromal Cell-Derived Factor-1 Polypeptides, Polynucleotides, Modulators Thereof and Methods of Use - diagram, schematic, and image 01 ...

Ubiquitination of the chemokine receptor CXCR4 serves as a targeting signal for lysosomal degradation, but the mechanisms mediating ubiquitination and lysosomal sorting remain poorly understood. Here we report that the Nedd4-like E3 ubiquitin ligase AIP4 mediates ubiquitination of CXCR4 at the plasm …

The chemokine SDF1 (stromal cell-derived factor 1) directs cell migration in many different contexts, ranging from embryogenesis to inflammation. SDF1a is the guidance cue for the zebrafish lateral line primordium, a tissue that moves along the flank of the embryo and deposits cells that form mechanosensory organs. The SDF1a receptor CXCR4b acts in cells at the leading edge of the primordium to direct its migration. Two new studies show that a second SDF1 receptor, CXCR7, is required only in the trailing cells of the primordium, and they explore how these two receptors orchestrate migration of the primordium. CXCR4b and CXCR7 are expressed in complementary domains, possibly through mutual repression in which each receptor inhibits expression of the other. These studies illustrate how the entire primordium can respond to a single signal, yet generate cell type-specific responses by using different receptors.. ...

TY - JOUR. T1 - Use of shRNA for stable suppression of chemokine receptor expression and function in human cancer cell lines. AU - Salazar, Nicole. AU - Muñoz, Daniel. AU - Hoy, James. AU - Lokeshwar, Bal L.. PY - 2014. Y1 - 2014. N2 - In this chapter, we describe a protocol used for stable silencing of chemokine receptor CXCR7 in human cancer cells using shRNA in a lipid transfection setting, previously published by our laboratory. We provide thorough detail and background information about the process of shRNA to clarify the importance of this process. We use CXCR7 shRNA and scrambled sequence shRNA constructs cloned into a pRS plasmid under the control of a U6 promoter for stable expression. Human cancer cells are transfected with shRNA-pRS using Lipofectamine 2000. Cells stably expressing the shRNA are selected from transfected cultures following 2 weeks in medium containing the selection antibiotic puromycin. The emergent cell colonies are evaluated for knockdown of CXCR7 mRNA and protein ...

Previous studies have demonstrated that the process of tumor metastasis is closely associated with EMT (24,25). The crucial feature of the EMT process is that epithelial cells lose cell-cell adhesion molecules, including E-cadherin (32,33), and express mesenchymal proteins, such as N-cadherin, to acquire motility (34), which could enhance the invasion of tumor cells into adjacent tissues and promote metastasis to distant sites (35). Numerous studies have also demonstrated that various signaling pathways are involved in the regulation of EMT in tumor cells or in the microenvironment (21,36-38). It has been well documented that the CXCL12/CXCR4 axis promotes EMT and metastasis in numerous different types of cancer cells. For example, the CXCL12/CXCR4 axis increases microRNA-125b expression and induces EMT in human colorectal cancer (21). Additionally, the overexpression of CXCL12 and CXCR4 in esophageal cancer stem cells accelerates esophageal tumor spread and metastasis (39). Conversely, blocking ...

Novel bio-reducible polymer compositions which combine the ability to act as a CXCR4 antagonist and simultaneously provide enhanced gene delivery through the formation of inert nanocarrier polyplexes have been developed. As would be expected for biodegradable polymers, the cytotoxicity of these nanocarrier compositions are very low with measured IC50 values 50 to 100 times higher than conventional polyethylenimines (PEI) controls. Significantly, the known CXCR4 antagonist drug AMD3100 has successfully been incorporated into the polymer composition and shown to retain activity comparable or better than the drug alone with or without the formation of a nanocarrier polyplexes. Successful gene delivery by the nanocarrier polyplexes has been demonstrated through fluorescence imaging studies and measurements of transfected gene expression levels. Preliminary results of two different animal studies confirm the CXCR4 antagonist response of this novel composition for both lung cancer metastasis and ...

Mice. Male 6- to 12-week-old WT BALB/cJ (CD45.2+), BALB/cByJ (CD45.2+), and syngeneic CByJ.SJL(B6)-Ptprca/J (CD45.1+) as well as WT C57BL/6J and syngeneic B6.SJL-Ptprca Pep3b/BoyJ (CD45.1+), WT DBA/2J, and FVB/NJ mice were purchased from the Jackson Laboratory. The knockout strains C.129S2(B6)-Cxcr2tm1Mwm/J (CXCR2-KO, BALB/cJ background), B6.FVB(Cg)-Mmp9tm1Tvu/J (MMP9-KO, C57BL/6J background), FVB.Cg-Mmp9tm1Tvu/J (MMP9-KO, FVB/NJ background), B6.129S7-Itgaltm1Bll/J (CD11a-KO, C57BL/6J background), and B6.129S4-Itgamtm1Myd/J (CD11b-KO, C57BL/6J background) were also obtained from Jackson Laboratory. Endothelial-specific CXCR2 ablated mice were generated by crossing C57BL/6-Cxcr2tm1Rmra/J (CXCR2fl/fl, Jackson Laboratory) and B6;129-Tg(Cdh5-cre)1Spe/J (Cdh5Cre, Jackson Laboratory) mice. Mobilization experiments were performed with Cxcr2fl/flCre+ mice (CXCR2fl/WTCre+ were used as controls) reconstituted with WT BM from syngeneic B6.SJL-Ptprca Pep3b/BoyJ (CD45.1+, Jackson Laboratory) donors. ...

Mice. Male 6- to 12-week-old WT BALB/cJ (CD45.2+), BALB/cByJ (CD45.2+), and syngeneic CByJ.SJL(B6)-Ptprca/J (CD45.1+) as well as WT C57BL/6J and syngeneic B6.SJL-Ptprca Pep3b/BoyJ (CD45.1+), WT DBA/2J, and FVB/NJ mice were purchased from the Jackson Laboratory. The knockout strains C.129S2(B6)-Cxcr2tm1Mwm/J (CXCR2-KO, BALB/cJ background), B6.FVB(Cg)-Mmp9tm1Tvu/J (MMP9-KO, C57BL/6J background), FVB.Cg-Mmp9tm1Tvu/J (MMP9-KO, FVB/NJ background), B6.129S7-Itgaltm1Bll/J (CD11a-KO, C57BL/6J background), and B6.129S4-Itgamtm1Myd/J (CD11b-KO, C57BL/6J background) were also obtained from Jackson Laboratory. Endothelial-specific CXCR2 ablated mice were generated by crossing C57BL/6-Cxcr2tm1Rmra/J (CXCR2fl/fl, Jackson Laboratory) and B6;129-Tg(Cdh5-cre)1Spe/J (Cdh5Cre, Jackson Laboratory) mice. Mobilization experiments were performed with Cxcr2fl/flCre+ mice (CXCR2fl/WTCre+ were used as controls) reconstituted with WT BM from syngeneic B6.SJL-Ptprca Pep3b/BoyJ (CD45.1+, Jackson Laboratory) donors. ...

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Recent work identified the murine gene homologous to the human T cell attracting chemokine CXC receptor ligand 11 (CXCL11, also termed I-TAC, SCYB11, ss-R1, H174, IP-9). Here, the biological activity and expression patterns of murine CXCL11 relative to CXCL9 (MIG) and CXCL10 (IP-10/crg-2), the other …

1. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382:635-8 2. Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature. 1998;393:591-4 3. Pelus LM, Fukuda S. Chemokine-mobilized adult stem cells; defining a better hematopoietic graft. Leukemia. 2008;22:466-73 4. Lapidot T, Dar A, Kollet O. How do stem cells find their way home?. Blood. 2005;106:1901-10 5. Massberg S, Schaerli P, Knezevic-Maramica I, Kollnberger M, Tubo N, Moseman EA. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell. 2007;131:994-1008 6. Hoggatt J, Pelus LM. Eicosanoid regulation of hematopoiesis and hematopoietic stem and progenitor trafficking. Leukemia. 2010;24:1993-2002 7. Ratajczak MZ, ...

Rabbit monoclonal antibody raised against synthetic protein of human CXCR3. A synthetic peptide corresponding to human CXCR3. (MAB22014) - Products - Abnova

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The antileukemic effect of inhibiting bromodomain and extra-terminal domain-containing (BET-containing) proteins (BETPs) such as BRD4 has largely been largely attributed to transcriptional downregulation of cellular anabolic and antiapoptotic processes, but its effect on the bone marrow microenvironment, a sanctuary favoring the persistence of leukemic stem/progenitor cells, is unexplored. Sustained degradation of BETP with the small-molecule BET proteolysis-targeting chimera (PROTAC) ARV-825 resulted in a marked downregulation of surface CXCR4 and CD44, key proteins in leukemia-microenvironment interactions, in acute myeloid leukemia (AML) cells. Abrogation of surface CXCR4 expression impaired SDF-1α-directed migration and was mediated through transcriptional downregulation of PIM1 kinase, which in turn phosphorylates CXCR4 and facilitates its surface localization. Downregulation of CD44, including isoforms CD44v8-10 impaired cystine uptake, lowered intracellular reduced glutathione, and ...

The antileukemic effect of inhibiting bromodomain and extra-terminal domain-containing (BET-containing) proteins (BETPs) such as BRD4 has largely been largely attributed to transcriptional downregulation of cellular anabolic and antiapoptotic processes, but its effect on the bone marrow microenvironment, a sanctuary favoring the persistence of leukemic stem/progenitor cells, is unexplored. Sustained degradation of BETP with the small-molecule BET proteolysis-targeting chimera (PROTAC) ARV-825 resulted in a marked downregulation of surface CXCR4 and CD44, key proteins in leukemia-microenvironment interactions, in acute myeloid leukemia (AML) cells. Abrogation of surface CXCR4 expression impaired SDF-1α-directed migration and was mediated through transcriptional downregulation of PIM1 kinase, which in turn phosphorylates CXCR4 and facilitates its surface localization. Downregulation of CD44, including isoforms CD44v8-10 impaired cystine uptake, lowered intracellular reduced glutathione, and ...

The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and ester forms of the nicotinamide glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. Ester forms of the nicotinamide glycolate antagonized CXCL1-stimulated chemotaxis (IC50 = 42 nM) and calcium flux (IC50 = 48 nM) in human neutrophils, but they were inactive in cell-free assays of 125I-CXCL8/CXCR2 binding and CXCL1-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) exchange. Acid forms of the nicotinamide glycolate were inactive in whole-cell assays of chemotaxis and calcium flux, but they inhibited 125I-CXCL8/CXCR2 binding and CXCL1-stimulated [35S]GTPγS exchange. The 3H ester was internalized by neutrophils and rapidly converted to the 3H ...

Plerixafor, also known as AMD3100, is a bicyclam with hematopoietic stem cell-mobilizing activity. Plerixafor blocks the binding of stromal cell-derived factor (SDF-1alpha) to the cellular receptor CXCR4, resulting in hematopoietic stem cell (HSC) release from bone marrow and HSC movement into the peripheral circulation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus). Plerixafor was approved by the U.S. Food and Drug Administration for this indication on December 15, 2008. In Europe, the drug was approved on 29 May 2009.

This protein belongs to family A of G protein-coupled receptor superfamily. The gene is preferentially expressed by immature dendritic cells and memory T cells. The ligand of this receptor is macrophage inflammatory protein 3 alpha (MIP-3 alpha). This receptor has been shown to be important for B-lineage maturation and antigen-driven B-cell differentiation, and it may regulate the migration and recruitment of dendritic and T cells during inflammatory and immunological responses. Alternatively spliced transcript variants that encode the same protein have been described for this gene.[6]. ...

TY - JOUR. T1 - Vectorial secretion of interleukin-8 mediates autocrine signalling in intestinal epithelial cells via apically located CXCR1. AU - Rossi, O.. AU - Karczewski, J.. AU - Stolte, E.H.. AU - Brummer, R.J.. AU - van Nieuwenhoven, M.A.. AU - Meijerink, M.. AU - van Neerven, R.J.J.. AU - van Ijzendoorn, S.C.. AU - van Baarlen, P.. AU - Wells, J.. PY - 2013. Y1 - 2013. N2 - BackgroundIn the intestinal mucosa, several adaptations of TLR signalling have evolved to avoid chronic inflammatory responses to the presence of commensal microbes. Here we investigated whether polarized monolayers of intestinal epithelial cells might regulate inflammatory responses by secreting IL-8 in a vectorial fashion (i.e. apical versus basolateral) depending on the location of the TLR stimulus.ResultsIn the Caco-2 BBE model of polarized villus-like epithelium, apical stimulation with TLR2 and TLR5 ligands resulted in the apical secretion of IL-8. The CXCR1 receptor for IL-8 was expressed only on the apical ...

The CXCR3 receptor has been identified as the gateway for permiability in celiac disease. A study published in the July issue of Gastroenterology identifies the CXCR3 receptor in the intestine as a gluten gateway. When people with celiac disease eat ...

The chemokine CXCL12/SDF1a has first been described in the immune system where it functions include chemotaxis for lymphocytes and macrophages, migration of hematopoietic cells from fetal liver to bone marrow and the formation of large blood vessels. Among other chemokines, CXCL12 has recently attracted much attention in the brain as it has been shown that it can be produced not only by glial cells but also by neurons. In addition, its receptors CXCR4 and CXCR7, which are belonging to the G-protein coupled receptors family, are abundantly expressed in diverse brain area, CXCR4 being a major co-receptor for human immunodeficiency virus (HIV)-1 entry. This chemokine system has been shown to play important roles in brain plasticity processes occurring during development but also in the physiology of the brain in normal and pathological conditions. For example, in neurons, CXCR4 stimulation has been shown regulate the synaptic release of glutamate and GABA. It can also act post-synaptically by activating a

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Laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) are common head and neck cancers with a high propensity for lymph node (LN) and lung metastasis. Here, we report that LHSCCs express high levels of functional CXCR4 receptors, native for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Primary tumor immunohistochemistry from LHSCC patients has revealed significant expression of CXCR4 and CXCL12. Greater expression of CXCR4 but not that of CXCL12 is correlated with LN and distant metastasis. Reverse transcription-polymerase chain reaction and western blots have demonstrated that CXCR4 messenger RNA (mRNA) and protein were expressed in LHSCC cell lines as well, but failed to detect CXCL12 mRNA expression. CXCL12 treatment enhanced extracellular signal-regulated kinase (ERK) pathway activation and the motility/invasiveness of LHSCC cell lines, which were blocked by treatment with a CXCR4 antagonist (AMD3100) and a specific MEK inhibitor (U0126). Results show that the mRNA and ...

Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activate a phosphatidylinositol-calcium second messenger system. This receptor binds to IL-8 with a high affinity and to MGSA (GRO) with a low affinity (By similarity).

Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. It is known that CXCR7, a second CXCL12 receptor, regulates TEM of CXCR4+CXCR7+ tumor cells towards a CXCL12 source. In this study, we set out to assess the potential stimulation by CXCL12 of tumor cell TEM towards other chemokines and whether CXCR7 might be able to regulate such effects. The human Burkitts lymphoma cell line NC-37, which expresses CXCR4, CXCR5, CXCR7 and CCR7, was selected as a model system. TEM of these cells through a human HUVEC endothelial cell monolayer was used as the main model system for these studies. Regulation of their TEM

Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. It is known that CXCR7, a second CXCL12 receptor, regulates TEM of CXCR4+CXCR7+ tumor cells towards a CXCL12 source. In this study, we set out to assess the potential stimulation by CXCL12 of tumor cell TEM towards other chemokines and whether CXCR7 might be able to regulate such effects. The human Burkitts lymphoma cell line NC-37, which expresses CXCR4, CXCR5, CXCR7 and CCR7, was selected as a model system. TEM of these cells through a human HUVEC endothelial cell monolayer was used as the main model system for these studies. Regulation of their TEM

Transmembrane signaling of the CXC chemokine stromal cell-derived factor-1 (SDF-1) is mediated by CXCR4, a G protein-coupled receptor initially identified in leukocytes and shown to serve as a coreceptor for the entry of HIV into lymphocytes. Characterization of SDF-1- and CXCR4-deficient mice has revealed that SDF-1 and CXCR4 are of vital developmental importance. To study the role of the SDF-1/CXCR4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cDNA encoding SDF-1 of the lower vertebrate Xenopus laevis (xSDF-1). Recombinant xSDF-1 was produced in insect cells, purified, and functionally characterized. Although xSDF-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)SDF-1alpha in terms of activating both X. laevis CXCR4 and hCXCR4. Thus, both xSDF-1 and hSDF-1alpha promoted CXCR4-mediated activation of heterotrimeric G(i2) in a cell-free system and induced release of intracellular calcium ions ...

The mechanisms responsible for the accumulation and persistence of T cell infiltrates within the rheumatoid synovium are poorly understood. In this study we set out to explore whether the aberrant expression of chemokine receptors on synovial T cells contributes to their persistence in chronic rheumatoid synovitis. Rheumatoid synovial T cells are highly differentiated primed cells that express high levels of β1 and β2 integrins as well as the inflammatory chemokine receptors CXCR3 and CCR5 (5, 7, 8, 14). Surprisingly, they also express high levels of the constitutive chemokine receptor CXCR4, whose expression has previously been thought to be confined to unprimed CD45RA+ T cells (19, 23). Removal of T cells from the synovial microenvironment led to loss of CXCR4 expression, which was regained after exposure to autologous SF, suggesting that the synovial microenvironment directly modifies the character of infiltrating T cells in the joint.. CXCR4 is expressed on a wide variety of cells and ...

Hematopoietic progenitor cells (HPCs) normally reside in the bone marrow (BM) but can be mobilized into the peripheral blood (PB) after treatment with GCSF or chemotherapy. In previous studies, we showed that granulocyte precursors accumulate in the BM during mobilization induced by either GCSF or cyclophosphamide (CY), leading to the accumulation of active neutrophil proteases in this tissue. We now report that mobilization of HPCs by GCSF coincides in vivo with the cleavage of the N-terminus of the chemokine receptor CXCR4 on HPCs resident in the BM and mobilized into the PB. This cleavage of CXCR4 on mobilized HPCs results in the loss of chemotaxis in response to the CXCR4 ligand, the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Furthermore, the concentration of SDF-1 decreased in vivo in the BM of mobilized mice, and this decrease coincided with the accumulation of serine proteases able to directly cleave and inactivate SDF-1. Since both SDF-1 and its receptor, CXCR4, are ...

Maedi visna virus (MVV) is a retrovirus that is member of the Lentivirus genus. MVV infects sheep and goats and causes progressive pneumonia or paralysis, leading to death. Since the discovery of the receptor for Human immunodeficiency virus (HIV), Simian immunodeficiency virus (SIV) and Feline immunodeficiency virus (FIV) all include the chemokine receptor CXCR4, it has been postulated that all members of the Lentivirus share a common mechanism of entry that involves the use of CXCR4. With the use of syncytia assays, infection-, inhibition- and enhancement studies, it was shown that CXCR4 is not a common lentivirus receptor. U87 and HOS cells, both celllines lacking CXCR4, were susceptible to infection. However, cells transfected with CD4 and CXCR4 showed an increased syncytia formation and the presence of CD¤ and CXCR4 augments virus-induced cell fusion. The nature of MVV receptor is still not known, but our data suggest the use of CD4 and/or CXCR4 as accessory molecules or as part of a ...

Other Development of an effective low-cost anti-acquired immunodeficiency syndrome (AIDS) drugs is needed for treatment of AIDS patients in developing countries. Host cell lipid raft microdomains, which are enriched with cholesterol, glycolipids, ceramide, and gangliosides, are important for human immunodeficiency virus type 1 (HIV-1) entry. Retinoid analogs have been shown to modulate ceramide levels in the cell membrane, while cholera toxin B subunit (CT-B) specifically binds to the ganglioside GM1. In this study, we found that the acyclic retinoid analogs geranylgeranoic acid (GGA) and NIK-333 as well as CT-B efficiently attenuate CXCR4-tropic, but not CCR5-tropic, HIV-1 vector infection. We also found that GGA and NIK-333 suppress CXCR4-tropic HIV-1 infection by attenuating CXCR4 expression. CT-B also attenuated CXCR4-tropic HIV-1 infection, but did not suppress CXCR4 expression. These results suggest a distinct role for lipid raft microdomains in CXCR4- and CCR5-tropic HIV-1 infections and ...

Abstract. [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS) is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R) antagonist. Unexpectedly, we identified that DLS also has the ability to block CXCL12 binding and activity through CXCR4 on T cells and peripheral blood mononuclear cells (PBMCs). Moreover, as CXCR4 has been shown to act as a major co-receptor for HIV-1 entry into CD4 positive host cells, we have also found that DLS partially blocks CXCR4-mediated HIV-1 entry and propagation in activated human PBMCs. These data demonstrate that DLS is not the specific and selective antagonist as thought for GHS-R1a and appears to have additional effects on the CXCR4 chemokine receptor. Our findings also suggest that structural analogues that mimic DLS binding properties may also have properties of blocking HIV infectivity, CXCR4 dependent cancer cell migration and attenuating chemokine-mediated immune cell trafficking in inflammatory disorders.. Keywords: CXCL12, CXCR4, ...

During development, Hedgehog (Hh) signaling controls both cell fate and proliferation, but how cells decide whether to divide or differentiate in response to signaling is not clear. Stückemann et al. report that, in the zebrafish gastrula, Hh signaling promoted proliferation of endoderm and inhibited proliferation of nonendodermal cells (mesoderm and ectoderm). Because the chemokine stromal cell-derived factor 1 (SDF-1) has been implicated in Hh-induced proliferation in other cell types, and because the SDF-1-activated G protein-coupled receptor CXCR4a is present in the endoderm, the authors investigated the role of CXCR4a in the context of early endoderm development. Hh signaling is induced when Hh binds to its transmembrane receptor Patched (Ptc), thus relieving Ptc-mediated repression of the transmembrane protein Smoothened (Smo), which initiates intracellular signal transduction. Knocking down Ptc, therefore, activates Hh signaling. In endodermal cells, morpholino-mediated knockdown of ...

CXC chemokine ligand 12 (CXCL12), or stromal cell-derived factor 1 (SDF1), is the only known natural ligand for the HIV-1 coreceptor, CXC chemokine receptor 4 (CXCR4). A single nucleotide polymorphism (SNP) in the CXCL12 gene (SDF1-3A) has been associated with disease progression to AIDS in some studies, but not others. Mutations in the CXCR4 gene are generally rare and have not been implicated in HIV-1/AIDS pathogenesis. This study analyzed the SDF1-3A SNP and performed mutation screening for polymorphic markers in the CXCR4 gene to determine the presence or absence of significant associations with susceptibility to HIV-1 infection. The study consisted of 257 HIV-1-seropositive patients and 113 HIV-1-seronegative controls representing a sub-Saharan African population belonging to the Xhosa ethnic group of South Africa. The SDF1-3A SNP was associated with an increased risk for HIV-1 infection (P = 0.0319) whereas no significant association was observed between the occurrence of the SDF1-3A SNP and

In the present work, we studied coreceptor usage by 11 primary HIV-2 isolates in U87.CD4 cells expressing chemokine receptors previously shown to function as coreceptors for HIV-1 (CCR1, CCR2b, CCR3, CCR5, and CXCR4) and in GHOST(3) cells expressing CCR5, CXCR4, or orphan receptors implicated in SIV infection (Bonzo and BOB) together with CD4. We found that 10 of 11 primary HIV-2 isolates were able to use CCR5. In contrast, only two isolates, both from patients with advanced disease, were able to efficiently use CXCR4. These two isolates also promptly induced syncytia in MT-2 cells, a pattern described for HIV-1 isolates using CXCR4. However, in contrast to HIV-1 isolates, many of the HIV-2 isolates were promiscuous in their coreceptor usage in that they were able to use, in addition to CCR5, one or more of the CCR1, CCR2b, CCR3, and BOB receptors. This result is in line with findings obtained by other groups (10, 20, 26, 36,44). Interestingly, the least promiscuous isolate, 1653, efficiently ...

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Suppression of the hosts immune system plays a major role in cancer progression. Tumor signaling of programmed death 1 (PD1) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of tumor immune escape. We sought to target these pathways in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood. Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit. RMS induced robust expansion of CXCR2+CD11b+Ly6Ghi MDSCs, and CXCR2 deficiency prevented CD11b+Ly6Ghi MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2+CD11b+Ly6Ghi MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also ...

摘要(Abstract)： 目的探讨不明原因复发性流产(URSA)患者绒毛中滤泡辅助性T(follicular helper T,Tfh)细胞相关因子白介素-21(interleukin-21,IL-21)、趋化因子受体-5(CXC chemokine receptor-5,CXCR5)、B细胞淋巴瘤分子6(B cell lymphoma 6,Bcl-6)和B淋巴细胞诱导成熟蛋白1(B lymphocyte-induced maturation protein 1,Blimp-1)的表达部位和表达水平及其与URSA发病的免疫学机制。方法收集30例URSA患者(URSA组)和30例要求人工流产的正常早孕妇女(对照组)绒毛组织,采用免疫组织化学法检测IL-21、CXCR5、Bcl-6和Blimp-1的表达情况,采用Pearson相关系数分析4种因子之间的相关性。结果 URSA组绒毛组织中IL-21、CXCR5、Bcl-6和Blimp-1表达水平明显高于对照组( ...

TY - JOUR. T1 - CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma. T2 - Analysis within a group of patients, all of whom developed lung metastasis. AU - Oda, Yoshinao. AU - Yamamoto, Hidetaka. AU - Tamiya, Sadafumi. AU - Matsuda, Shuichi. AU - Tanaka, Kazuhiro. AU - Yokoyama, Ryohei. AU - Iwamoto, Yukihide. AU - Tsuneyoshi, Masazumi. PY - 2006/5/1. Y1 - 2006/5/1. N2 - The chemokine, CXCL12, and its receptor, CXCR4, have recently been shown to play an important role in metastasis of several kinds of carcinoma. It has also been demonstrated that VEGF regulates both the expression of CXCR4 and invasiveness in breast cancer cell lines. We compared the immunohistochemical expression of CXCR4 and VEGF between the primary site and a concordant pulmonary metastatic site in 30 osteosarcoma patients, all of which had undergone thoracotomy. Microvessel density (MVD) as shown by immunostaining of CD34 and proliferative activity with MIB-1 monoclonal antibody was ...

Link to Pubmed [PMID] - 28181493. Nat Commun 2017 02;8:14253. Plasmacytoid dendritic cells (pDC) are specialized in secretion of type I interferon in response to pathogens. Here we show that natural monoamines and synthetic amines inhibit pDC activation by RNA viruses. Furthermore, a synthetic analogue of histamine reduces type I interferon production in a mouse model of influenza infection. We identify CXC chemokine receptor 4 (CXCR4) as a receptor used by amines to inhibit pDC. Our study establishes a functional link between natural amines and the innate immune system and identifies CXCR4 as a potential on-off switch of pDC activity with therapeutic potential.. https://www.ncbi.nlm.nih.gov/pubmed/28181493 ...

In Response: We read with interest Dr. von Luettichaus letter about the expression of chemokine receptors in osteosarcoma patient samples. They analyzed chemokine receptor expression in osteosarcoma tumor samples following microdissection. Their results showed that infiltrating cells and not the tumor cells per se represented the major source of expression of chemokine receptors, including CXCR4.. However, other data suggest that the osteosarcoma cells are expressing CXCR4 and other chemokine receptors. We previously analyzed the chemokine receptor expression by real-time PCR in different osteosarcoma cell lines. CXCR4 was expressed in two cell lines, U2OS and HOS, as reported by others (1-3). In their recent study, Kim et al. reported that K7M2 murine osteosarcoma cell lines expressed CXCR4. The cells were treated in vitro with a CXCR4 inhibitor (CTCE-9908). They observed a decrease in the proliferative rate, an increase in apoptosis, and a decrease in adhesion to extracellular matrix ...

Histone acetylation along with DNA methylation is the main epigenetic process that influences nociceptive gene expression in pain states identified to this point. Transcription-restrictive heterochromatin is converted to transcription-permissive euchromatin by histone acetylation and results in enhanced gene expression. Recently, several pain-related chemokine receptors and its relevant ligands are demonstrated to be epigenetically regulated via histone acetylation.13,44-46 The chemokine CCL2/monocyte chemoattractant protein-1 was shown separately to contribute to mechanical sensitization after surgical incision.45 Likewise, CXCR2 was of particular interest to us as this gene has been linked to nociceptive sensitization in several other studies.13,18,19 In the current study, we showed that both CXCR2 and its ligand KC were significantly increased in spinal cord tissue after incision when histone deacetylation was blocked. Furthermore, the relevant population of CXCR2 receptors probably resides ...

The protein encoded by this gene is a receptor for C-C type chemokines. It belongs to family 1 of the G protein-coupled receptors. This receptor binds and responds to a variety of chemokines, including eotaxin (CCL11), eotaxin-3 (CCL26), MCP-3 (CCL7), MCP-4 (CCL13), and RANTES (CCL5). It is highly expressed in eosinophils and basophils, and is also detected in TH1 and TH2 cells, as well as in airway epithelial cells. This receptor may contribute to the accumulation and activation of eosinophils and other inflammatory cells in the allergic airway. It is also known to be an entry co-receptor for HIV-1. This gene and seven other chemokine receptor genes form a chemokine receptor gene cluster on the chromosomal region 3p21. Alternatively spliced transcript variants have been described. [provided by RefSeq, Sep 2009 ...

TY - JOUR. T1 - CXCR5-dependent entry of CD8 T cells into rhesus macaque B-cell follicles achieved through T-cell engineering. AU - Ayala, Victor I.. AU - Deleage, Claire. AU - Trivett, Matthew T.. AU - Jain, Sumiti. AU - Coren, Lori V.. AU - Breed, Matthew W.. AU - Kramer, Joshua A.. AU - Thomas, James A.. AU - Estes, Jacob. AU - Lifson, Jeffrey D.. AU - Ott, David E.. PY - 2017/6/1. Y1 - 2017/6/1. N2 - Follicular helper CD4 T cells, TFH, residing in B-cell follicles within secondary lymphoid tissues, are readily infected by AIDS viruses and are a major source of persistent virus despite relative control of viral replication. This persistence is due at least in part to a relative exclusion of effective antiviral CD8 T cells from B-cell follicles. To determine whether CD8 T cells could be engineered to enter B-cell follicles, we genetically modified unselected CD8 T cells to express CXC chemokine receptor 5 (CXCR5), the chemokine receptor implicated in cellular entry into B-cell follicles. ...

Receptor for a C-C type chemokine. Binds to eotaxin, MCP-3, MCP-4 and RANTES and subsequently transduces a signal by increasing the intracellular calcium ions level.

Rationale: We have previously shown that neutrophils from Chronic Obstructive Pulmonary Disease (COPD) patients migrate with reduced accuracy (Sapey et al. AJRCCM 2011; 183:1176-86). There is some evidence to suggest chemokine receptors may be differentially in COPD neutrophils. We sought to determine if differences in receptor function may explain the aberrant neutrophilic migration in COPD.. Methods: Surface expression of CXCR1, CXCR2 and the fMLP receptor (FPR1) was semi quantified by Fluorescence Activated Cell Sorting (FACS) before and at points throughout a 2 hour stimulation time-course with IL-8 or fMLP. CXCR1 and CXCR2 shedding was quantified by ELISA and localisation was assessed by fluorescence microscopy on adhered and fixed neutrophils following stimulation with fMLP.. Results: CXCR1 was significantly lower in quiescent COPD neutrophils compared to health. This difference was rapidly abolished following stimulation with IL-8. No differences were observed in CXCR2 or FPR1 expression. ...

TY - JOUR. T1 - Elimination of senescent neutrophils by TNF-related apopotosis-inducing ligand. AU - Lum, Julian J.. AU - Bren, Gary. AU - McClure, Rebecca. AU - Badley, Andrew D.. PY - 2005/7/15. Y1 - 2005/7/15. N2 - Neutrophils are phagocytic effectors which are produced in the bone marrow and released into the circulation. Thereafter, they are either recruited to sites of inflammation or rapidly become senescent, return to the bone marrow, and undergo apoptosis. Stromal cell-derived factor 1 (SDF-1) coordinates the return of senescent neutrophils to the bone marrow by interacting with CXCR4 that is preferentially expressed on senescent neutrophils. We demonstrate that CXCR4 ligation by SDF-1 or other CXCR4 agonists significantly increases the expression of both TNF-related apopotosis-inducing ligand (TRAIL) and of the death-inducing TRAIL receptors on neutrophils, which confers an acquired sensitivity to TRAIL-mediated death and results in TRAIL-dependent apoptosis. In vivo administration of ...

The laboratory of Douglas Fearon is seeking an outstanding postdoc fellow for research on the interaction between the immune system and pancreatic cancer. Our laboratory discovered that immune suppression in the tumor microenvironment of an autochthonous model of pancreatic ductal adenocarcinoma is capable of preventing cancer cell-specific CD8+ T cells from controlling tumor growth (Feig, et al, PNAS 2013). Inhibition is mediated by the interaction of the stromal cell-derived chemokine, CXCL12, with its receptor, CXCR4, on T cells prevents them from accumulating in the tumor. We are studying three aspects of this problem: how CXCL12 associates with cancer cells to protect them from immune attack; how this CXCL12 stimulates CXCR4 on T cells to suppress their influx into tumors; and the identification of new CXCR4 antagonists that will overcome this suppressive effect of CXCR4. We have also developed a new model of pancreatic cancer metastases that has uncovered a remarkable effect of adaptive immunity

This gene encodes a multi-pass membrane protein that belongs to the CXC chemokine receptor family. It is expressed in mature B-cells and Burkitts lymphoma. This cytokine receptor binds to B-lymphocyte chemoattractant (BLC), and is involved in B-cell migration into B-cell follicles of spleen and Peyer patches. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011 ...

An attempt to replicate the results seen in the really functionally cured Berlin Patient did not result in a second person cured of HIV.. It resulted in yet another HIV death.. How? If HIV needs CCR5, and they replaced this patients bone marrow with cells that could not make CCR5, how did he die from AIDS?. Because while HIV likes CCR5 as a co-receptor to infect cells… it doesnt need it. The natural diversity of a patients quasispecies will contain some variants of HIV that can use a different co-receptor, CXCR4.. Viruses that use CXCR4 are assholes.. In this second patient, the radiation/chemo did not kill all of the cells latently infected with CXCR4-tropic viruses. When those viruses woke up in their new environment, and no CCR5-tropic viruses as competition, they went nuts. Oh, and they must have also been resistant to antiretrovirals. For more complications.. So, yeah, the attempt to generate another Berlin Patient, another person functionally cured of HIV!… lead to a mans ...

AMD11070 is a new chemical entity that inhibits HIV-1 entry by binding specifically and reversibly to CXCR4, a coreceptor required by T-tropic virus for membrane fusion and entry into cells. The purpose of this study is to evaluate the safety and relative antiretroviral activity of AMD11070 in HIV-infected individuals who have demonstrated X4 -tropic virus in their plasma. With the ongoing development of other fusion and entry inhibitors and the need for alternative treatment options in patients (especially those with multidrug resistant virus), the demonstration of activity and safety of AMD11070 represents a potentially important advance in antiretroviral therapeutics. This will be the first study that determines the therapeutic potential of anti-CXCR4 compounds in HIV-infected patients.. Note: Study was previously suspended due to non-clinical reports of hepatotoxicity and histologic findings. Study has been completed. ...

Stromal cell-derived factor-1 beta (SDF-1 β), also called CXCL12b, is one of two SDF-1 splice variants made by a wide variety of cells upon stimulation by inflammatory cytokines such as TNF, IL-1, and LPS. SDF-1 β signals through the G protein-coupled receptor CXCR4 to recruit activated leukocytes.

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Recombinant Murine Stromal Cell-Derived Factor-1 alpha (rMu SDF-1 alpha) is a recently discovered protein belonging to the alpha-chemokine (C-X-C) family of cytokines. Creative Bioarrays recombinant murine SDF-1 alpha is a 7.9 kDa protein containing 68 amino acid residues ...

Polyclonal antibody for GRO alpha/CXCL1 detection. Host: Rabbit.Size: 100μg/vial. Tested applications: WB. Reactive species: Human. GRO alpha/CXCL1 information: Molecular Weight: 11301 MW; Subcellular Localization: Secreted.

Chemokine cooperativity has previously been suggested to be caused by convergence of intracellular signaling pathways downstream of receptor activation (5-7, 11, 12). Our data indicate that chemokine cooperativity is not strictly dependent on the receptor of the cooperative chemokine. For example, mtCXCL12 and mtCXCL11 fully activate their respective G protein-coupled receptors (Supplemental Fig. 4) but do not cooperate with CCL21 (Fig. 4). Furthermore, RT-PCR analyses and cAMP measurements indicated that CHO-CCX-CKR cells do not express CXCR5 or CXCR4, the cognate Gαi-coupled receptors for CXCL13 and CXCL12, respectively (data not shown). Our data concur with previous evidence suggesting that activation of the receptor for the cooperative chemokine is not necessary for cooperativity (8, 9).. Alternatively, chemokine cooperativity has been suggested to originate from chemokine heterodimerization (9, 10). Our observation that both monomeric and dimeric CXCL12 species can induce chemokine ...

Autologous cell therapy with bone marrow (BM)-derived pro-angiogenic cells is a promising new treatment modality to enhance ischemic recovery after myocardial infarction. However, the introduction into the clinical mainstream is hampered by technical challenges with cell procurement, handling, selection, expansion and application. In this issue of Circulation, Jujo et al. show that mobilization of endogenous cells by a clinically approved drug inhibiting the CXCR4 receptor improves myocardial recovery after infarction in a mouse model of ischemia/reperfusion (IR).1 ...

TY - JOUR. T1 - Increased frequency of cytotoxic CXCR5+effector memory CD8+T cells during natural control of HIV-1 infection. AU - Adams, P.. AU - Iserentant, G.. AU - Servais, J-Y. AU - Pannus, P.. AU - Rutsaert, S.. AU - Van Frankehuijsen, M.. AU - De Wit, S.. AU - Allard, S. D.. AU - Messiaen, P.. AU - Moutschen, M.. AU - Aerts, J. L.. AU - Vandekerckhove, L.. AU - Vanham, G.. AU - Devaux, C.. N1 - NPP. PY - 2019. Y1 - 2019. M3 - Conference abstract in journal. VL - 20. SP - 42. EP - 43. JO - HIV Medicine. JF - HIV Medicine. SN - 1464-2662. ER - ...

Expression of CXCR5 (BLR1, CD185, MDR15) in bone marrow tissue. Antibody staining with HPA042432 and CAB026149 in immunohistochemistry.

Expression of CXCR1 (CD181, CDw128a, CKR-1, CMKAR1, IL8RA) in stomach tissue. Antibody staining with HPA031991 in immunohistochemistry.

The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in the recruitment of immune and inflammatory cells as successfully demonstrated in the airways using agents that block either CXCL12 or CXCR4 (Hachet-Haas et al JBC 2008). We here highlight the unique relationship between pharmacokinetics and anti-asthmatic activity of chalcone 4, a CXCL12 neutraligand. Balb/c mice were sensitized (OVA+alum) and challenged (OVA or solvent, i.n., D17-20). Chalc4 or vehicle were administered i.n. 2h before each challenge. Chalc4 reduces airway hyperresponsiveness measured by whole body plethysmography (45±7%) and Flexivent® (37±5%), as well as eosinophilia (54±2%), IL5 (75±6% ) and mucus (84±2%) in BAL and lung collagen (78±8%). IgE in plasma and IL4 in BALF are not changed, indicating a downstream effect on sensitization. In addition, chalc4 reduces recruitment of M1 macrophages (62±4%), and their production of TNFα in response to CXCL12 (98±4%). In parallel, chalc4 significantly ...

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BioAssay record AID 52555 submitted by ChEMBL: Compound was tested in vitro for inhibition of [125I]RANTES binding to THP-1 cell membranes rich in C-C chemokine receptor type 1.

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