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.