Inhibition of indoleamine 2,3-dioxygenase in human macrophages inhibits interferon-gamma-induced bacteriostasis but does not abrogate toxoplasmastasis

Induction of indoleamine 2,3-dioxygenase (IDO) by IFN-gamma results in grow th inhibition of Toxoplasma and Chlamydia spp. as well as tumor cells. This is caused by the degradation, and therefore depletion, of L-tryptophan nec essary for cell protein synthesis. Human macrophages stimulated with IFN-ga mma express IDO and inhibit the growth of intracellular toxoplasma and chla mydia as well as that of extracellular bacteria such as group B streptococc i. Here we describe experiments in which the L-tryptophan analog, 6-chloro- DL-tryptophan (CDLT) caused a dose-dependent inhibition in the IFN-gamma-in duced IDO-mediated L-tryptophan degradation in monocyte-derived macrophages and glioblastoma cells. An inhibition of IDO activity of up to 80 % was ob served at concentrations of CDLT of 750 mu M. Expression of IDO at this con centration, as shown by Northern blot analysis, was unimpaired. This inhibi tion of IDO was coupled in glioblastoma cells by a complete abrogation of t he IFN-gamma-induced toxoplasmastasis in these cells. IDO inhibition by CDL T in human macrophages resulted in a complete abrogation of the IFN-gamma-i nduced growth inhibition of streptococci and staphylococci. In contrast to this, IFN-gamma-induced toxoplasmastasis was not inhibited in human macroph ages by CDLT-mediated IDO inhibition.