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

Journal Article · Mon Feb 01 04:00:00 EST 1988 · Proc. Natl. Acad. Sci. U.S.A.; (United States)

DOI:https://doi.org/10.1073/pnas.85.4.1242· OSTI ID:6618909

Ozaki, Y; Edelstein, M P; Duch, D S

The antiproliferative effects of interferon ..cap alpha.. (IFN-..cap 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 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-..cap 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-..cap 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.

• Research Organization: Wellcome Research Labs., Research Triangle Park, NC (USA)
• OSTI ID: 6618909
• Journal Information: Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 85:4; ISSN PNASA
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES
AMINO ACIDS
ANIMAL CELLS
AROMATICS
AZAARENES
AZOLES
BIOLOGICAL EFFECTS
CARBON 14 COMPOUNDS
CARBOXYLIC ACIDS
CARCINOMAS
CELL PROLIFERATION
DISEASES
DOSE-RESPONSE RELATIONSHIPS
EMBRYONIC CELLS
ENZYME INDUCTION
ENZYMES
GENE REGULATION
GROWTH FACTORS
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
INDOLES
INTERFERON
LABELLED COMPOUNDS
LYMPHOKINES
MITOGENS
NEOPLASMS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXIDOREDUCTASES
OXYGENASES
PROTEINS
PYRROLES
TRYPTOPHAN
TUMOR CELLS