Interferon gamma induced production of indoleamine 2,3 dioxygenase in cultured human synovial cells.
OBJECTIVE
Synovial membrane cells from inflamed joints share morphological and functional properties with malignant mesenchymal cells. Interferon gamma (IFN-gamma) has antitumor cell activity related to stimulation of 2,3 indoleamine dioxygenase (IDO), a widely distributed tryptophan catabolizing enzyme. Our objective was to measure synoviocyte IDO production to determine if the varied clinical and in vitro effects of IFN-gamma on nonmalignant immunocompetent cells might involve a similar mechanism.


METHODS
Using an established radioenzymatic assay, we measured IDO activity in suspensions of freshly isolated cells obtained by enzymatic dispersion of human synovial membrane, and in fresh and longterm (> or = 2 months) cultures of these cells in response to varying concentrations of recombinant human interferons alpha 2a, beta ser, or gamma.


RESULTS
In fresh and in > or = 2 month-old cultures, IFN-gamma strongly stimulated IDO activity, a corresponding fall in supernatant tryptophan levels, and an elevation in the supernatant concentration of kynurenine, tryptophan's principal metabolite, mRNA for IDO was likewise markedly increased in cells after 4 days' incubation with IFN-gamma. Staining studies indicated that the IDO producing cells in synovium were not typical macrophages. Interferon beta ser had weak IDO stimulatory activity that was in a few cases additive to that of IFN-gamma. In no case did interferon beta ser abrogate IFN-gamma induced IDO activity increases. Interferon alpha 2a also had weak stimulatory activity.


CONCLUSIONS
IFN-gamma stimulates IDO production and tryptophan metabolism in cultured human synovial cells, and therefore may contribute to this cytokine's in vitro and clinical effects in arthritis and inflammation.
Malone
D G
DG
Department of Medicine, University of Wisconsin, Madison.
Dolan
P W
PW
Brown
R R
RR
Kalayoglu
M V
MV
Arend
R A
RA
Byrne
G I
GI
Ozaki
Y
Y
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007477:Ions; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D013194:Staining and Labeling; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000096:biosynthesis* / Q000235:genetics; D015032:Zinc / Q000494:pharmacology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; D007477:Ions; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000068576:Interferon beta-1b; D016899:Interferon-beta; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D015032:Zinc; D000068556:Interferon beta-1a