Inhibition of CCR5 expression by IL-12 through induction of beta-chemokines in human T lymphocytes.
IL-12 induces initiation of the differentiation of naive CD4+ T lymphocytes into Th1 cells and is important for the control of cell-mediated immunity. beta-Chemokines serve to attract various types of blood leukocytes to sites of infection and inflammation. The specific receptor for the beta-chemokines (macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES), CCR5, also functions as the primary coreceptor for macrophage-tropic isolates of HIV-1. IL-12, but not IL-4, IL-10, or IL-13, now has been shown to down-modulate the surface expression of CCR5 induced by IL-2 on both CD4+ and CD8+ T lymphocytes. Decreased CCR5 surface expression was not secondary to transcriptional inhibition, given that CCR5 mRNA was enhanced in cells cultured in IL-12/IL-2 compared with those cultured in IL-2 only. The effect of IL-12 in down-modulation of CCR5 surface expression was shown to be mediated by soluble factors secreted from the T cells. Rapid and transient intracellular Ca2+ mobilization was induced in monocytes by IL-12-induced supernatants, which desensitized the response of monocytes to MIP-1alpha, but not their response to stromal cell-derived factor-1alpha. Neutralization with specific Abs identified these factors as MIP-1alpha and MIP-1beta from most donors. IL-4, IL-10, IFN-gamma, and IL-18 primarily inhibited MIP-1beta secretion and also weakly suppressed MIP-1alpha secretion. HIV-1 replication was inhibited in IL-2/IL-12-containing cultures that correlated with chemokine and chemokine-receptor levels. These data suggest that the effects of IL-12 on beta-chemokine production and chemokine-receptor expression may contribute to the immunomodulatory activities of IL-12 and may have potential therapeutic relevance in controlling HIV-1 replication.
Wang
J
J
Laboratory of Cell and Viral Regulation, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, National Institutes of Health, Bethesda, MD 20892, USA. wangj@cber.fda.gov
Guan
E
E
Roderiquez
G
G
Norcross
M A
MA
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism*; D015536:Down-Regulation; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008264:Macrophages / Q000821:virology; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D014158:Transcription, Genetic; D014779:Virus Replication / Q000187:drug effects
D019742:Chemokines, CC; D020382:Interleukin-18; D019713:Receptors, CCR5; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D002118:Calcium