title: CXC chemokine receptor 4 expression and function in human astroglioma cells.
abstract: Chemokines constitute a superfamily of proteins that function as chemoattractants and activators of leukocytes. Astrocytes, the major glial cell type in the CNS, are a source of chemokines within the diseased brain. Specifically, we have shown that primary human astrocytes and human astroglioma cell lines produce the CXC chemokines IFN-gamma-inducible protein-10 and IL-8 and the CC chemokines monocyte chemoattractant protein-1 and RANTES in response to stimuli such as TNF-alpha, IL-1beta, and IFN-gamma. In this study, we investigated chemokine receptor expression and function on human astroglioma cells. Enhancement of CXC chemokine receptor 4 (CXCR4) mRNA expression was observed upon treatment with the cytokines TNF-alpha and IL-1beta. The peak of CXCR4 expression in response to TNF-alpha and IL-1beta was 8 and 4 h, respectively. CXCR4 protein expression was also enhanced upon treatment with TNF-alpha and IL-1beta (2- to 3-fold). To study the functional relevance of CXCR4 expression, stable astroglioma transfectants expressing high levels of CXCR4 were generated. Stimulation of cells with the ligand for CXCR4, stromal cell-derived factor-1alpha (SDF-1alpha), resulted in an elevation in intracellular Ca(2+) concentration and activation of the mitogen-activated protein kinase cascade, specifically, extracellular signal-regulated kinase 2 (ERK2) mitogen-activated protein kinase. Of most interest, SDF-1alpha treatment induced expression of the chemokines monocyte chemoattractant protein-1, IL-8, and IFN-gamma-inducible protein-10. SDF-1alpha-induced chemokine expression was abrogated upon inclusion of U0126, a pharmacological inhibitor of ERK1/2, indicating that the ERK signaling cascade is involved in this response. Collectively, these data suggest that CXCR4-mediated signaling pathways in astroglioma cells may be another mechanism for these cells to express chemokines involved in angiogenesis and inflammation.
authors.affiliation: Department of Cell Biology, University of Alabama, Birmingham, AL 35294, USA. joh@uab.edu
authors.forename: J W
authors.initials: JW
authors.lastname: Oh
authors.forename: K
authors.initials: K
authors.lastname: Drabik
authors.forename: O
authors.initials: O
authors.lastname: Kutsch
authors.forename: C
authors.initials: C
authors.lastname: Choi
authors.forename: A
authors.initials: A
authors.lastname: Tousson
authors.forename: E N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D001254:Astrocytoma / Q000276:immunology* / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D007424:Intracellular Fluid / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D017154:Stromal Cells / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D002070:Butadienes; C515255:CXCL12 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D016209:Interleukin-8; D009570:Nitriles; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium