Mechanism of interferon-gamma action. Characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-gamma and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity

• Published in: The Journal of biological chemistry Vol. 263; no. 4; pp. 2041 - 2048
• Main Authors: Takikawa, O, Kuroiwa, T, Yamazaki, F, Kido, R
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 05.02.1988; American Society for Biochemistry and Molecular Biology
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Ascorbic Acid - metabolism; Biological and medical sciences; Carcinoma, Squamous Cell - enzymology; Enzyme Induction; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Immunosorbent Techniques; Interferon-gamma - pharmacology; Lung - drug effects; Methylene Blue - metabolism; Miscellaneous; Osteosarcoma - enzymology; Oxygenases - metabolism; Recombinant Proteins - pharmacology; Regulatory factors and their cellular receptors; Tryptophan - metabolism; Tryptophan Oxygenase - metabolism; Tumor Cells, Cultured - drug effects; Human; Cell proliferation; Cell culture; Purification; Enzyme; Induction; Lung; Tryptophan; Monoclonal antibody; Degradation; Placenta; Indoleamine 2,3-dioxygenase; Inhibition; Fibroblast; Gamma interferon
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(19)77982-4

Induction by interferon-gamma of indoleamine 2,3-dioxygenase (a tryptophan degradation enzyme) was examined with 11 human cell lines. The enzyme induction was demonstrated in 7 of the 11 cell lines. The induced enzyme in each of the 7 cell lines was identical to the enzyme purified from human placenta, as evidenced by immunoblot analysis with a monoclonal antibody specific to the placental one. The extent of the induction varied largely with the cell line; a relatively high induction was observed with HEL (lung fibroblasts), NY (osteosarcoma), and A-431 (epidermoid carcinoma). The enzyme induction was dependent on the concentration of interferon-gamma and occurred 12-18 h after addition of interferon-gamma to the cultures. Interferon-alpha or -beta was completely ineffective in this induction. Interferon-gamma inhibited the growth of the 7 cell lines observed with the enzyme induction, and this growth inhibition was accompanied with a complete deletion of tryptophan (less than 1 microM) in the culture medium by the induction of the enzyme. For two of these cell lines, the inhibition was partially reversed by an addition of exogenous tryptophan to the medium not to be depleted. These findings indicated that the growth inhibition by interferon-gamma was in part explained by the tryptophan depletion in the medium caused by the enzyme induction.