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

The antiproliferative effects of interferon α (IFN-α) and interferon γ (IFN-γ) were found to be cell-dependent. Among the human cell lines examined, IFN-γ 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 of 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-α- or vehicle-treated cells, virtually all of this amino acid was depleted in the medium of the IFN-γ-treated group following 2-3 days of culture. Supplementing the growth medium with additional L-tryptophan reversed the antiproliferative effect of IFN-γ against KB cells in a dose- and time-dependent manner. The antiproliferative effects of IFN-α and IFN-γ 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-γ in WiDr cells suggest multiple mechanisms of action of the IFNs. The data show that the antiproliferative effect of IFN-γ through induction of indoleamine 2,3-dioxygenase, with a consequent L-tryptophan deprivation, is an effective means of regulating cell growth