Abstract
Peripheral blood lymphocytes express CCR5, a chemokine receptor for immune cell migration and calcium signaling that serves as an important coreceptor for the HIV. After in vitro stimulation, CCR5 expression is dramatically increased on mature T lymphocytes, especially on the CD45RO+ memory subset. In this study, we report that TNF-alpha delays the surface expression of CCR5 on PBLs after activation and diminishes CCR5 irrespective of its initial level. Functional loss of CCR5 is reflected in a decreased capability of the treated cells to migrate and signal calcium after MIP-1beta stimulation. The effect is mediated via the p80 type II TNF receptor (TNFR2), which induces NF-kappaB among other factors, leading to an enhanced secretion of the chemokines macrophage-inflammatory protein-1alpha, macrophage-inflammatory protein-1beta, and RANTES. Expression of these chemokines directly down-regulates CCR5. These findings reveal a new regulatory mechanism utilized by activated peripheral T cells to modulate their chemotaxis and potentially other functions mediated by CCR5, including the infection of T lymphocytes by macrophage-tropic HIV strains.
MeSH terms
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Antibodies / pharmacology
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Antigens, CD / physiology
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Binding, Competitive / immunology
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CCR5 Receptor Antagonists
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Calcium Signaling / immunology
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Cell Migration Inhibition
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Chemokine CCL4
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Chemokine CCL5 / antagonists & inhibitors
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Chemokine CCL5 / immunology
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Chemokine CCL5 / metabolism
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Chemokines, CC / blood*
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Chemokines, CC / metabolism*
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Chemotaxis, Leukocyte / immunology
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Down-Regulation / immunology
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Humans
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Lymphocyte Activation / immunology
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Lymphocytes / metabolism*
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Macrophage Inflammatory Proteins / antagonists & inhibitors
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Macrophage Inflammatory Proteins / immunology
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Macrophage Inflammatory Proteins / metabolism
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NF-kappa B / physiology
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Receptors, CCR5 / biosynthesis*
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Receptors, CCR5 / blood*
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Receptors, Tumor Necrosis Factor / physiology
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Receptors, Tumor Necrosis Factor, Type II
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Signal Transduction / immunology
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Tumor Necrosis Factor-alpha / physiology*
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Up-Regulation / immunology
Substances
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Antibodies
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Antigens, CD
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CCR5 Receptor Antagonists
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Chemokine CCL4
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Chemokine CCL5
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Chemokines, CC
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Macrophage Inflammatory Proteins
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NF-kappa B
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Receptors, CCR5
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type II
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Tumor Necrosis Factor-alpha