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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The differentiation of B lymphocytes in the bone marrow is guided by the surrounding microenvironment determined by cytokines, adhesion molecules, and the extracellular matrix. These microenvironmental factors are mainly provided by stromal cells. In this paper, we report the identification of a VCAM-1-positive stromal cell population by flow cytometry. This population showed the expression of cell surface markers known to be present on stromal cells (CD10, CD13, CD90, CD105) and had a fibroblastoid phenotype in vitro. Single cell RT-PCR analysis of its cytokine expression pattern revealed transcripts for haematopoietic cytokines important for either the early B lymphopoiesis like flt3L or the survival of long-lived plasma cells like BAFF or both processes like SDF-1. Whereas SDF-1 transcripts were detectable in all VCAM-1-positive cells, flt3L and BAFF were only expressed by some cells suggesting the putative existence of different subpopulations with distinct functional properties. In summary, the VCAM-1-positive cell population seems to be a candidate stromal cell population supporting either developing B cells and/or long-lived plasma cells in human bone marrow.
Mol Immunol 2007 Mar
PMID:VCAM-1-positive stromal cells from human bone marrow producing cytokines for B lineage progenitors and for plasma cells: SDF-1, flt3L, and BAFF. 1706 79

The chemokine receptor CCR2 binds four pro-inflammatory monocyte chemoattractant proteins, designated MCP1/CCL2, MCP2/CCL8, MCP3/CCL7 and MCP4/CCL13. This study demonstrates the important biology of this receptor during the response to the chemokine milieu. Competitive chemotaxis and calcium flux assays were performed utilising mixtures of chemokines to assess a hierarchal arrangement of chemokine prepotency; these demonstrated that the MCP2-CCR2 interaction is able to supersede signals generated by RANTES, another pro-inflammatory chemokine, or the homeostatic chemokine SDF1. These observations were validated using three physiologically relevant monocytic cell lines. Having identified the importance of CCR2, experiments were then performed to examine the signal transduction processes coupled to this receptor. G protein coupling was initially examined; Cholera toxin reduced the chemotactic response to MCP2 (p<0.001), whilst the response to the other MCP chemokines remained normal. The response to MCP2 was uniquely inhibited by elevated concentrations of cAMP and, unlike MCP1, 3 and 4 (p<0.05), MCP2 failed to inhibit adenylate cyclase. Expression of dominant negative H-ras demonstrated that each MCP chemokine required active ras in order to elicit ERK activation and a chemotactic response. Unlike MCP1, MCP2 failed to induce nuclear translocation of activated ERK1 or subsequent induction of c-Myc expression. Akt activation also showed ligand-specific differences, with MCP2 producing a delayed response compared to the other MCP chemokines. Together these data highlight the importance of CCR2 and suggest that it is a powerful tool for fine tuning the immune response.
Mol Immunol 2007 Mar
PMID:Chemokine-mediated inflammation: Identification of a possible regulatory role for CCR2. 1708 10

Renal cell carcinoma (RCC) is characterized by organ-specific metastases. The chemokine stromal derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 have been suggested to regulate organ-specific metastasis in various other cancers. On this basis, we hypothesized that the biological axis of CXCL12 via interaction with its receptor, CXCR4, is a major mechanism for RCC metastasis. We demonstrated that CXCR4 was significantly expressed on circulating cytokeratin+ RCC cells from patients with known metastatic RCC. We detected up-regulation of CXCR4 mRNA and protein levels on a human RCC cell line by either knockdown of the von Hippel-Lindau (VHL) tumor suppressor protein, or incubating the cells under hypoxic conditions. The enhanced CXCR4 expression was mediated through the interaction of the Hypoxia Inducible Factor-1alpha (HIF-1alpha) with the promoter region of the CXCR4 gene. Furthermore, the expression of CXCR4 on human RCC directly correlated with their metastatic ability in vivo in both heterotopic and orthotopic SCID mouse models of human RCC. Neutralization of CXCL12 in SCID mice abrogated metastasis of RCC to target organs expressing high levels of CXCL12; without altering tumor cell proliferation, apoptosis, or tumor-associated angiogenesis. Therefore, our data suggest that the CXCL12/CXCR4 biological axis plays an important role in regulating the organ-specific metastasis of RCC.
Mol Cancer 2006 Nov 03
PMID:Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. 1708 23

The chemokine CXCL12, also known as stromal cell-derived factor-1 (SDF-1), is a small protein that regulates leukocyte trafficking and is variably expressed in a number of normal and cancer tissues. CXCL12 as ligand and its receptor CXCR4 have been implicated in colorectal cancer (CRC) progression including angiogenesis and metastasis. A CXCL12 gene variant CXCL12-A (CXCL12-G801A, a single nucleotide polymorphism in the 3' untranslated region) is associated with increased susceptibility to breast cancer. Based on the suggested role of CXCL12 in the pathogenesis of cancer we examined the association of the gene variant CXCL12-A with CRC. The polymorphism was analysed with PCR and RFLP methods. Furthermore, the plasma CXCL12 levels from patients with CRC were also examined. There was no significant difference in genotype distribution and allelic frequencies between CRC patients (n=151) and controls (n=141). On the other hand, we found that the carrying rate of allele CXCL12-A was higher in colon cancer patients compared with rectal cancer patients (P=0.017). Analyses by ELISA showed that CRC patients (n=63) had a lower CXCL12 plasma level compared with controls (P<0.0001). Moreover, patients with tumours classified as Dukes' stage B and C revealed lower levels than patients with tumours in Dukes' stage A. Further studies with larger samples of patients are necessary to determine whether the CXCL12 polymorphism and plasma level reflect the clinical outcome of CRC and have an impact on CRC progression.
Int J Mol Med 2007 Jan
PMID:Polymorphism and circulating levels of the chemokine CXCL12 in colorectal cancer patients. 1714 42

Stromal cell-derived factor (SDF-1) is a CXC chemokine that selectively activates the CXCR4 chemokine receptor. Fibronectin is an intracellular matrix component that binds integrin and mediates cell-matrix adhesion. Activation of the integrin receptor can occur in two ways: by ligand binding (outside-in signaling), and in response to intracellular events (inside-out signaling). In the current study we showed that SDF-1a inhibited adhesion of T lymphocyte Jurkat cells resulting from binding high concentrations of fibronectin as well as that of THP-1 monocytes. The effect of SDF-1a on fibronectin-mediated adhesion was partly reversed by the CXCR4 receptor antagonist T140. Our results suggest that an SDF-1/ CXCR4 signal pathway modulates fibronectin-mediated lymphocytes adhesion.
Mol Cells 2006 Dec 31
PMID:The chemokine SDF-1alpha suppresses fibronectin-mediated in vitro lymphocytes adhesion. 1720 59

In addition to their physiologic effects in inflammation and angiogenesis, chemokines are involved in cancer pathology. The aim of this study was to determine whether the chemokine stromal cell-derived factor 1 (SDF-1) induces the growth, migration, and invasion of human hepatoma cells. We show that SDF-1 G protein-coupled receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), and SDF-1 mRNA are expressed in human hepatoma Huh7 cells, which secrete and bind SDF-1. This binding depends on CXCR4 and glycosaminoglycans. SDF-1 associates with CXCR4, and syndecan-4 (SDC-4), a heparan sulfate proteoglycan at the plasma membrane of Huh7 cells, induces the growth of Huh7 cells by promoting their entry into the cell cycle, and inhibits the tumor necrosis factor-alpha-mediated apoptosis of the cells. SDF-1 also reorganizes Huh7 cytoskeleton and induces tyrosine phosphorylation of focal adhesion kinase. Finally, SDF-1 activates matrix metalloproteinase-9, resulting in increased migration and invasion of Huh7 cells. These biological effects of SDF-1 were strongly inhibited by the CXCR4 antagonist AMD3100, by a glycosaminoglycan, heparin, as well as by beta-D-xyloside treatment of the cells, or by c-jun NH(2)-terminal kinase/stress-activated protein kinase inhibitor. Therefore, the CXCR4, glycosaminoglycans, and the mitogen-activated protein kinase signaling pathways are involved in these events. The fact that reducing SDC-4 expression by RNA interference decreased SDF-1-induced Huh7 hepatoma cell migration and invasion strongly indicates that SDC-4 may be an auxiliary receptor for SDF-1. Finally, the fact that CXCR4 is expressed in hepatocellular carcinoma cells from liver biopsies indicates that the in vitro results reported here could be extended to in vivo conditions.
Mol Cancer Res 2007 Jan
PMID:Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. 1725 44

Bone marrow derived endothelial progenitor cells (EPC) improve endothelial function and neoangiogenesis. Prostaglandin E1 (PGE1) is used for the treatment of patients with peripheral artery disease (PAD). However, the molecular effects are only partially understood. Treatment of C57/Bl6 mice with PGE1, 10 microg/kg BW increased the number of circulating Sca-1/VEGFR-2 positive EPC in the blood compared to vehicle (122+/-7% and 119+/-6% after 10 and 20 days). EPC in the bone marrow were upregulated to 125+/-11% (10 days) and 142+/-15% (20 days). PGE1 increased DiLDL/Lectin positive spleen-derived EPC to 170+/-20% and 174+/-14% after 10 and 20 days. Treatment with PGE1 enhanced in-vivo neoangiogenesis by 2-fold (disk assay, 218+/-27%). PGE1 enhanced the SDF-1 induced migratory capacity per number of EPC to 140+/-11%, 146+/-22% and 160+/-16% after 10, 14 and 20 days. Greater migratory capacity was associated with upregulation of expression of telomere repeat-binding factor (TRF2). EPC of PGE1-treated mice were characterized by reduced apoptosis. Similarly, PGE1 prevented H(2)O(2)-induced apoptosis in cultured human EPC. The effect is mediated by PI3-kinase. The effects of PGE1 on EPC were completely prevented by co-treatment with the NO-inhibitor L-NAME, 50 mg kg(-1) p.o. Treatment with the prostaglandin I2 derivative iloprost (10 microg/kg BW, 20 days) did not alter EPC numbers or function. Physical exercise is the basis of the treatment of patients with PAD. Voluntary running increased EPC numbers in mice. Treatment with PGE1 resulted in an additional increase of Sca-1/VEGFR-2- and DiLDL/lectin positive EPC as well as migration. n=10-24 for all groups, all effects p<0.05. In summary, prostaglandin E1 increases the number of EPC in the blood and the bone marrow in mice. The effect is additive to physical exercise, depends on nitric oxide and is characterized by reduction of PI3-kinase mediated apoptosis. PGE1-mediated upregulation of EPC is associated with improved EPC function and enhanced angiogenesis.
J Mol Cell Cardiol 2007 Mar
PMID:Regulation of endothelial progenitor cells by prostaglandin E1 via inhibition of apoptosis. 1729 26

Keratinocyte growth factor (KGF) is a critical growth factor in lung development and is a protective agent after lung injury, although the exact mechanisms of this protective effect have not yet been elucidated. Our laboratory has shown that circulating epithelial progenitor cells can traffic to the airway and that they appear to be derived from the bone marrow. On this basis, we hypothesized that KGF and its putative receptor (KGFR) would be important to these cells. We showed that the KGFR, which is found almost exclusively on epithelial cells, was present on cells in the bone marrow and circulation of mice that identified a subpopulation of cytokeratin 5+ circulating epithelial progenitor cells (CEPC). In addition, the KGFR co-localized with a population of cytokeratin 5+ basal cells in the repairing proximal airway. Systemic administration of KGF resulted in a significant increase in mobilization of cytokeratin 5+ CEPC at 6 h after injection. Administration of KGF to mouse recipients of heterotopic syngeneic tracheal transplants resulted in protection and more rapid repair of the tracheal epithelium, with an increase in the number of CEPC in the epithelium of the airway, and this effect was abrogated by blocking CEPC with anti-CXCL12 antibodies. KGF therefore appears to be an important growth factor for local resident progenitor epithelial cell repair and for mobilization and enhanced engraftment of CEPC to the injured proximal airway epithelium.
Am J Respir Cell Mol Biol 2007 Jul
PMID:Keratinocyte growth factor improves repair in the injured tracheal epithelium. 1733 41

Chemokines are small secreted proteins with chemoattractant properties for immune cells. Besides their role in the immune system, chemokines and their receptors may play important roles in the central nervous system. Neurodegenerative disorders that involve neuroinflammation such as multiple sclerosis, stroke, Alzheimer's disease, Parkinson's disease and HIV-associated dementia are commonly associated with local upregulation and release of chemokines. However, recent work has established that certain chemokines, constitutively expressed in the brain, exert functions in the brain that are distinct from inflammation. These chemokines regulate neuronal migration during brain development, modulate neuronal activity and play a role in various neurodegenerative diseases, pain and more recently in neuroendocrine functions. All these novel aspects, mainly focused on the chemokine stromal cell-derived factor-1/CXCL12 and its receptor CXCR4, were presented by pioneers in the field during the symposium held at the sixth International Congress of Neuroendocrinology in Pittsburgh, Pennsylvania, USA in June 2006.
J Mol Endocrinol 2007 Mar
PMID:Chemokines as modulators of neuroendocrine functions. 1733 97

Chemotactic cytokines (chemokines) are small secreted proteins that control leukocyte trafficking in immune organs. Chemokines which are induced in the brain during conditions of inflammation play a role in the local immune response. Recently, it has been established in the rodent brain that distinct chemokines and chemokine receptors are constitutively expressed by neurons and that these chemokines modulate neuronal functions. The CXC motif chemokine stromal cell-derived factor-1 (SDF-1), CXCL12 together with its cognate receptor CXCR4 represents the best-characterized neuronal chemokine system. Transwell migration assays with neuronal precursors, pharmacological manipulation of CXCR4 signaling in embryonic brain explants, and histochemical studies of SDF-1- or CXCR4-deficient mouse embryos provide proof that SDF-1 directs neuronal migration and axonal pathfinding in the developing nervous system. In the adult brain, SDF-1 is thought to influence neurogenesis as well as recruitment of brain resident and non-resident circulating cells toward sites of lesion. The present review summarizes patterns and functions of the SDF-1/CXCR4 system in the rodent brain with a focus on the developing and adult cerebral cortex.
J Mol Endocrinol 2007 Mar
PMID:CXC chemokine receptor 4 regulates neuronal migration and axonal pathfinding in the developing nervous system: implications for neuronal regeneration in the adult brain. 1733


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