Induction of indoleamine 2,3-dioxygenase in tumor cells transplanted into allogeneic mouse: interferon-gamma is the inducer.
Tryptophan depletion observed during induction of indoleamine 2,3-dioxygenase (IDO) in cultured cells has been suggested to involve a mechanism identical to that employed in self-defense against inhaled microorganisms and tumor growth. We recently reported that a dramatic induction of IDO occurred in i.p. transplanted tumor (Meth-A) cells undergoing rejection from allogeneic mice (C57BL/6), and that soluble factor(s) released from infiltrated host cells was responsible for the IDO induction. Here we report on the characterization of the soluble factor. To assay the factor, we used a 35 mm special culture dish (Transwell), which consisted of two wells divided vertically with a membrane (0.4 micron pore). Host cells (mainly lymphocytes) that infiltrated into the transplantation loci were cultured in the upper well, and untreated Meth-A cells in the lower well. With this in vitro system, the membrane-permeable factor, released by the host cells (upper well), induced IDO in the tumor cells (lower well). The culture superna tants, obtained by centrifuging the culture media from the upper and lower wells, contained the IDO inducer. The inducer activity was completely neutralized by the addition of antibody against interferon-gamma (IFN-gamma) but not by antibody against IFN-alpha/beta. The concentration of IFN-gamma in the medium after 1-day culture with a Transwell culture dish was found to be 2-3 U/ml based on the neutralization curve with the antibody. At this concentration, recombinant IFN-gamma induced IDO in Meth-A cells to the same extent as the inducer in the culture medium. These observations indicate that the in vivo factor for IDO induction in the allografted tumor cells is IFN-gamma.
Takikawa
O
O
Department of Cell Biology, Osaka Bioscience Institute, Japan.
Habara-Ohkubo
A
A
Yoshida
R
R
D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D006084:Graft Rejection; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000502:physiology*; D007737:Kynurenine / Q000096:biosynthesis; D051379:Mice; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000473:pathology; D014184:Transplantation, Homologous; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000637:transplantation
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase