title: Transforming growth factor-beta1 increases CXCR4 expression, stromal-derived factor-1alpha-stimulated signalling and human immunodeficiency virus-1 entry in human monocyte-derived macrophages.
abstract: Stromal-derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 play crucial roles in leukocyte migration and activation, as well as embryogenesis, angiogenesis, cancer and viral pathogenesis. CXCR4 is one of the major human immunodeficiency virus-1 (HIV-1) coreceptors on macrophages. In many tissues macrophages are one of the predominant cell types infected by HIV-1 and act as a reservoir for persistent infection and viral dissemination. In patients infected by HIV-1, blood and tissue levels of transforming growth factor-beta1 (TGF-beta1) are increased. The purpose of this study was to evaluate the effects of TGF-beta1 on CXCR4 expression and function in primary human monocyte-derived macrophages (MDMs) and rat microglia. TGF-beta1 up-regulated CXCR4 and enhanced SDF-1alpha-stimulated ERK1,2 phosphorylation in these cells. The increased CXCR4 expression in human MDMs resulted in increased susceptibility of the cells to entry by dual-tropic CXCR4-using HIV-1 (D-X4). In contrast, TGF-beta1 failed to increase CCR5 expression or infection by a CCR5-using virus in MDMs. Our data demonstrate that TGF-beta1 enhances macrophage responsiveness to SDF-1alpha stimulation and susceptibility to HIV-1 by selectively increasing expression of CXCR4. The results suggest that increased expression of CXCR4 on macrophages may contribute to the emergence of dual-tropic X4 viral variants at later stages of HIV-1 infection.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610-0267, USA.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Chen
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Tuttle
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Oshier
authors.forename: Harm J
authors.initials: HJ
authors.lastname: Knot
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Streit
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Goodenow
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Harrison
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D017628:Microglia; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D051381:Rats; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases