Interferon-γ upregulates CCR5 expression in cord and adult blood mononuclear phagocytes

Divisions of Neonatology, the Clinical Immunology Laboratories, The Children's Hospital of Philadelphia, Philadelphia, PA
Blood (Impact Factor: 10.45). 03/1999; 93(4):1137-44.
Source: PubMed


The C-C chemokine receptors CCR5 and CCR3 are fusion coreceptors for human immunodeficiency virus (HIV) entry into macrophages. The regulation of their expression influences infectivity by HIV. We report here that interferon-gamma (IFN-gamma) a cytokine that has bidirectional effects on HIV infection of macrophages, significantly upregulated CCR5 and CCR3 cell surface expression in human mononuclear phagocytes isolated from placental cord blood and adult peripheral blood. Monocytes treated with IFN-gamma showed increased chemotaxis to the CCR5 ligands macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta, confirming the functional relevance of IFN-gamma-induced CCR5 expression. However, IFN-gamma suppressed HIV entry into macrophages. Interestingly, we demonstrated that IFN-gamma inhibited cell surface expression of CD4, the major receptor for HIV. This finding may explain the suppressive effect of IFN-gamma on HIV entry into macrophages, despite its enhancing effect on the expression of CCR5 and CCR3 by these cells. In addition, IFN-gamma-induced secretion of C-C chemokines (RANTES, MIP-1alpha, and MIP-1beta) by mononuclear phagocytes may also suppress HIV entry into macrophages. These data provide further evidence for cytokine-mediated regulation of CCR5 expression and are consistent with a novel paradigm in which cytokines regulate HIV infection and leukocyte migration by reciprocal and opposing effects on the expression of CD4 and chemokine receptors.

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    • "Cytokine levels are also known to affect CCR5. Cytokines affect CCR5 expression with pro-inflammatory cytokines such as interleukin 2 (IL-2) (Wu et al., 1997; Bleul et al., 1997), interleukin 12 (IL-12), tumor necrosis factor α and INF-γ increasing CCR5 expression on peripheral blood mononuclear cells (Hariharan et al., 1999; Patterson et al., 1999). The anti-inflammatory cytokine, interleukin 10 (IL-10), also increased CCR5 density on monocytes by prolonging the half-life of CCR5 mRNA (Sozzani et al., 1998). "
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    • "These inferences correlate with the up-regulation of CCL4 (or MIP-1b) (Schrum et al., 1996) and the reduced expression of EBF1, an activator of B-lineage gene expression (Roessler et al., 2007). Transcription and secretion of CCL4 by mononuclear phagocytes is induced by IFNγ (Hariharan et al., 1999), and its product is chemotactic for T helper1 cells (Siveke and Hamann, 1998) and a co-activator of MDMs (Dorner et al., 2002). OSMR encodes for an oncostatin M-specific receptor beta that is specifically activated by oncostatin M (OSM) (Mosley et al., 1996). "
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    • "TNFα, IL-1β and IFN-γ down-regulate both surface and total CD4 expression in primary human macrophages at the level of transcription [36,38-41]. TNFα, IFN-β, and IFN-γ inhibit R5 and R5/X4 HIV-1 entry into primary macrophages via down-regulation of both cell surface CD4 and CCR5 and via enhanced secretion of C-C chemokines, MIP-1α, MIP-1β, and RANTES [37,38,40,42-46]. An iterative pre-treatment of primary macrophages with TNFα prior to HIV infection inhibits HIV-1 replication [43]. "
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