Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDS.
Tryptophan (Trp) is an indispensable amino acid required for biosynthesis of proteins, serotonin and niacin. Indoleamine 2,3-dioxygenase (IDO) is induced by infections, viruses, lipopolysaccharides, or interferons (IFNs) and this results in significant catabolism of Trp along the kynurenine (Kyn) pathway. Intracellular growth of Toxoplasma gondii and Chlamydia psittaci in human fibroblasts in vitro is inhibited by IFN-gamma and this inhibition is negated by extra Trp in the medium. Similarly, growth of a number of human cell lines in vitro is inhibited by IFN-gamma and addition of extra Trp restores growth. Thus, in some in vitro systems, antiproliferative effects of IFN-gamma are mediated by induced depletion of Trp. We find that cancer patients given Type I or Type II IFNs can induce IDO which results in decreased serum Trp levels (20-50% of pretreatment) and increased urinary metabolites of the Kyn pathway (5 to 500 fold of pretreatment). We speculate that in vivo antineoplastic effects of IFNs and clinical side effects are mediated, at least in part, by a general or localized depletion of Trp. In view of reported increases of IFNs in autoimmune diseases and our earlier findings of elevated urinary Trp metabolites in autoimmune diseases, it seems likely that systemic or local depletion of Trp occurs in autoimmune diseases and may relate to degeneration, wasting and other symptoms in such diseases. We find high levels of IDO in cells isolated from synovia of arthritic joints. IFNs are also elevated in human immunodeficiency virus (HIV) patients and increasing IFN levels are associated with a worsening prognosis. We propose that IDO is induced chronically by HIV infection, is further increased by opportunistic infections, and that this chronic loss of Trp initiates mechanisms responsible for the cachexia, dementia, diarrhea and possibly immunosuppression of AIDS patients. In these symptoms, AIDS resembles classical pellagra due to dietary deficiency of Trp and niacin. In preliminary studies, others report low levels of Trp and serotonin, and elevated levels of Kyn and quinolinic acid in AIDS patients. The implications of these data in cancer, autoimmune diseases and AIDS are discussed.
Brown
R R
RR
Department of Human Oncology, University of Wisconsin Medical School, Madison 53792.
Ozaki
Y
Y
Datta
S P
SP
Borden
E C
EC
Sondel
P M
PM
Malone
D G
DG
D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007369:Interferon Inducers / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000502:physiology*; D007376:Interleukin-2 / Q000494:pharmacology; D007737:Kynurenine / Q000096:biosynthesis; D008297:Male; D009369:Neoplasms / Q000378:metabolism*; D009525:Niacin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007369:Interferon Inducers; D007376:Interleukin-2; D009525:Niacin; D012701:Serotonin; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D007372:Interferons; D014366:Tryptophan Oxygenase