Abstract
The chemokine stromal cell-derived factor (SDF)-1 and its receptor, CXCR4, play important roles in human immunodeficiency virus type 1 (HIV-1) pathophysiology, leukocyte trafficking, inflammation, hematopoiesis, embryogenesis, angiogenesis, and cancer metastasis. The effects of cytokines on the regulation of CXCR4 function were investigated in human primary monocytes-macrophages. The expression of functional CXCR4 on the cell surface was demonstrated by the detection of ligand-induced Ca(2+) mobilization, chemotaxis, and ligand-induced receptor endocytosis. Surface CXCR4 expression was down-regulated by cytokines interleukin-4 (IL-4), IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and up-regulated by IL-10 and transforming growth factor-beta 1. Down-regulation was mediated post-translationally, in the absence of protein degradation, through an endocytotic mechanism. In contrast to SDF-1 alpha-induced CXCR4 endocytosis, cytokine-induced endocytosis of this receptor was independent of actin filament polymerization. GM-CSF increased the expression of G protein-coupled receptor kinase 3 (GRK3), beta-arrestin-1, Pyk2, and focal adhesion kinase (FAK). Cytokine treatment also increased the total and tyrosine-specific phosphorylation of CXCR4 as well as the phosphorylation of FAK on tyrosine 397. It also induced the formation of GRK3.CXCR4 or FAK.CXCR4 complexes. Infection of macrophages by primary R5X4 and X4 isolates of HIV-1 was inhibited by IL-4, IL-13, and GM-CSF, an effect that was associated with down-regulation of surface CXCR4 expression. These data indicate that ligand-dependent and ligand-independent endocytoses of CXCR4 are mediated by different mechanisms. Cytokine-induced endocytosis of chemokine receptors may be of therapeutic value in HIV-1 infection, inflammation, tumor metastasis, and defective hematopoiesis.
Highlights
From the Laboratory of Gene Regulation, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892
Three types of human immunodeficiency virus type 1 (HIV-1) isolates that infect macrophages have been identified and differ according to the chemokine receptor targeted for use as a viral coreceptor: (i) R5 viruses infect macrophages and primary CD4ϩ T cells through CCR5 and constitute the principal virus type transmitted in vivo, as indicated by the resistance to HIV-1 infection of individuals who lack functional CCR5(3–5). (ii) Primary X4 viruses that have not been subjected to extensive passage in vitro use CXCR4 as a coreceptor and infect primary CD4ϩ T cells, T cell lines, and macrophages [6]
We have previously shown that cytokines and growth factors influence R5 HIV-1 infection in human primary monocyte-derived macrophages (MDMs) or T lymphocytes through modulation of CCR5 expression in both ligand-dependent [11] and ligand-independent [12] manners
Summary
Vol 276, No 52, Issue of December 28, pp. 49236 –49243, 2001 Printed in U.S.A. Role of Tyrosine Phosphorylation in Ligand-independent Sequestration of CXCR4 in Human Primary Monocytes-Macrophages*. The effects of cytokines on the regulation of CXCR4 function were investigated in human primary monocytes-macrophages. Cytokine treatment increased the total and tyrosine-specific phosphorylation of CXCR4 as well as the phosphorylation of FAK on tyrosine 397 It induced the formation of GRK31⁄7CXCR4 or FAK1⁄7CXCR4 complexes. Infection of macrophages by primary R5X4 and X4 isolates of HIV-1 was inhibited by IL-4, IL-13, and GM-CSF, an effect that was associated with down-regulation of surface CXCR4 expression. These data indicate that ligand-dependent and ligand-independent endocytoses of CXCR4 are mediated by different mechanisms. Cytokine-induced endocytosis of chemokine receptors may be of therapeutic value in HIV-1 infection, inflammation, tumor metastasis, and defective hematopoiesis
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