Interferon Type I and II Antagonism: A Novel Regulatory Mechanism of Indoleamine Dioxygenase Induction in Human Peripheral Blood Monocytes and Peritoneal Macrophages
Antiproliferative effects of interferon (IFN)-γ in vitro on some tumor cells (de 1a Maza and Peterson, 1988; Ozaki et al., 1988a; Takikawa et al., 1988), Chlamvdia psittaci (Byrne et al., 1986) and Toxoplasma gondii (Pfefferkorn, 1984) are mediated by deprivation of tryptophan (TRP) which results when the cytokine induces indoleamine 2, 3-dioxygenase (IDO) activity in the cancer or host cells. Among the human peripheral blood mononuclear cells as well as granulocytes, IFN-mediated induction of IDO is localized in peripheral blood monocytes (PBM) or PBM-derived macrophages (DM; Ozaki et al., 1987a; Werner et al., 1987; Rubin et al., 1988; Carlin et al., 1989), however the mechanism of control of extra-hepatic TRP metabolism by the IFNs has not been fully elucidated in these cells or in peritoneal macrophages (PM). The occurrence of IFN type I antagonism against IFN type II-elicited release of H202, expression of 1a antigen as well as mannosyl/fucosyl receptors, high-affinity binding of type II IFN, and tumor cell killing by macrophages has been reported (Ling et al., 1985; Ezekowitz et al., 1986; Garotta et al., 1986; Inaba et al., 1986; Pace 1987; Yoshida et al., 1988). However, the down-regulation of IFN-7-mediated induction of IDO by IFN-α, IFN-β and 12-0-tetradecanoylphorbol-13 acetate (TPA) has never been documented. To this end, we report clear differences between PBMs, DMs and PMs in response to IFNs as well as to a potent tumor promoter, TPA. Further, the occurrence of a novel regulatory mechanism of TRP metabolism through modulation of type II IFN-induced IDO activity by type I IFNs or by TPA, in monocytes and macrophages is demonstrated in this report.
KeywordsPeritoneal Macrophage Murine Macrophage Tumor Cell Killing Human Peripheral Blood Mononuclear Cell Human Peripheral Blood Monocyte
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