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).
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.
Available from: Michael S. Pepper
- "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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ABSTRACT: When HIV was initially discovered as the causative agent of AIDS, many expected to find a vaccine within a few years. This has however proven to be elusive; it has been approximately 30 years since HIV was first discovered, and a suitable vaccine is still not in effect. In 2009, a paper published by Hutter et al. reported on a bone marrow transplant performed on an HIV positive individual using stem cells that were derived from a donor who was homozygous for a mutation in the CCR5 gene known as CCR5 delta-32 (Δ32) (Hütter et al., 2009). The HIV positive individual became HIV negative and remained free of viral detection after transplantation despite having halted anti-retroviral (ARV) treatment. This review will focus on CCR5 as a key component in HIV immunity and will discuss the role of CCR5 in the control of HIV infection.
Available from: Robin Everts
- "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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ABSTRACT: Brucellosis is a worldwide zoonotic infectious disease that has a significant economic impact on animal production and human public health. We characterized the gene expression profile of B. abortus-infected monocyte-derived macrophages (MDMs) from naïve cattle naturally resistant (R) or susceptible (S) to brucellosis using a cDNA microarray technology. Our data indicate that (1) B. abortus induced a slightly increased genome activation in R MDMs and a down-regulated transcriptome in S MDMs, during the onset of infection, (2) R MDMs had the ability to mount a type 1 immune response against B. abortus infection which was impaired in S cells, and (3) the host cell activity was not altered after 12 h post-B. abortus infection in R MDMs while the cell cycle was largely arrested in infected S MDMs at 12 h p.i. These results contribute to an improved understanding of how host responses may be manipulated to prevent infection by brucellae.
Available from: Audrey Varin
- "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 . "
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ABSTRACT: Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-gamma display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease.
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