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