TNF-alpha-induced secretion of C-C chemokines modulates C-C chemokine receptor 5 expression on peripheral blood lymphocytes.
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.
Hornung
F
F
Laboratory of Immunology and Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Scala
G
G
Lenardo
M J
MJ
D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D001667:Binding, Competitive / Q000276:immunology; D065100:CCR5 Receptor Antagonists; D020013:Calcium Signaling / Q000276:immunology; D002464:Cell Migration Inhibition; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D019742:Chemokines, CC / Q000097:blood* / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000097:blood*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
D000906:Antibodies; D015703:Antigens, CD; D065100:CCR5 Receptor Antagonists; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D019713:Receptors, CCR5; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha