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 lymphocyt es into Thl cells and is important for the control of cell-mediated immunit y, beta-Chemokines serve to attract various types of blood leukocytes to si tes of infection and inflammation. The specific receptor for the beta-chemo kines (macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTE S), CCR5, also functions as the primary coreceptor for macrophage-tropic is olates of HIV-1, IL-12, but not IL-4, IL-10, or IL-13, now has been shown t o down-modulate the surface expression of CCR5 induced by IL-2 on both CD4( +) and CD8(+) T lymphocytes, Decreased CCR5 surface expression was not seco ndary to transcriptional inhibition, given that CCR5 mRNA was enhanced in c ells 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 transie nt intracellular Ca2+ mobilization was induced in monocytes by IL-12-induce d supernatants, which desensitized the response of monocytes to MIP-1 alpha , but not their response to stromal cell-derived factor-1 alpha. Neutraliza tion with specific Abs identified these factors as MIP-1 alpha and MIP-1 be ta from most donors. IL-4, IL-10, IFN-gamma, and IL-18 primarily inhibited MIP-1 beta secretion and also weakly suppressed MIP-1 alpha secretion. HIV- 1 replication was inhibited in IL-2/IL-12-containing cultures that correlat ed with chemokine and chemokine-receptor levels. These data suggest that th e effects of IL-12 on beta-chemokine production and chemokine-receptor expr ession may contribute to the immunomodulatory activities of IL-12 and may h ave potential therapeutic relevance in controlling HIV-1 replication.