Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma.

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Abstract
The antiproliferative effects of interferon .alpha. (IFN-.alpha.) and interferon .gamma. (IFN-.gamma.) were found to be cell-dependent. Among the human cell lines examined, IFN-.gamma. had a greater antiproliferative effect against cell lines that exhibited induction of indoleamine 2,3-dioxygenase, such as the KB oral carcinoma or WiDr colon adenocarcinoma, than against those that lacked the enzyme activity, such as the SW480 colon adenocarcinoma or NCI-H128 small-cell lung carcinoma. Induction of this dioxygenase showed a clear temporal relationship with increased metabolism of L-tryptophan and the depletion of this amino acid in the culture medium. While 70-80% of L-tryptophan remained in the medium of IFN-.alpha.- or vehicle-treated cells, virtually all of this amino acid was depleted in the medium of the IFN-.gamma.-treated group following 2-3 days of culture. Supplementing the growth medium with additional L-tryptophan reversed the antiproliferative effect of IFN-.gamma.-against KB cells in a dose- and time-dependent manner. The antiproliferative effects of IFN-.alpha. and IFN-.gamma. on SW480 and NCI-H128 cells, which are independent of the dioxygenase activity, and the inability of added L-tryptophan to reverse the effects of IFN-.gamma. in WiDr cells suggest multiple mechanisms of action of the IFNs. The data show that the antiproliferative effect of IFN-.gamma. through induction of indoleamine 2,3-dioxygenase, with a consequent L-tryptophan deprivation, is an effective means of regulating cell growth.