Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma.
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.
D002455:Cell Division / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010105:Oxygenases / Q000096:biosynthesis*; D013268:Stimulation, Chemical; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D009363:Neoplasm Proteins; D007371:Interferon-gamma; D014364:Tryptophan; D010105:Oxygenases; D014366:Tryptophan Oxygenase