Inhibition of CCR5 Expression by IL-12 Through Induction of β-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. β-Chemokines serve to attract various types of blood leukocytes to sites of infection and inflammation. The specific receptor for the β-chemokines (macrophage-inflammatory protein (MIP)-1α, MIP-1β, 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-1α, but not their response to stromal cell-derived factor-1α. Neutralization with specific Abs identified these factors as MIP-1α and MIP-1β from most donors. IL-4, IL-10, IFN-γ, and IL-18 primarily inhibited MIP-1β secretion and also weakly suppressed MIP-1α 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 β-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.