INTERFERON-GAMMA-INDUCED PRODUCTION OF INDOLEAMINE 2,3-DIOXYGENASE INCULTURED HUMAN SYNOVIAL-CELLS

Objective. Synovial membrane cells from inflamed joints share morpholo gical and functional properties with malignant mesenchymal cells. Inte rferon gamma (IFN-gamma) has antitumor cell activity related to stimul ation of 2,3 indoleamine dioxygenase (IDO), a widely distributed trypt ophan catabolizing enzyme. Our objective was to measure synoviocyte ID O production to determine if the varied clinical and in vitro effects of IFN-gamma on nonmalignant immunocompetent cells might involve a sim ilar mechanism. Methods. Using an established radioenzymatic assay, we measured IDO activity in suspensions of freshly isolated cells obtain ed by enzymatic dispersion of human synovial membrane, and in fresh an d longterm (greater than or equal to 2 months) cultures of these cells in response to varying concentrations of recombinant human interferon s alpha 2a, beta(ser), or gamma. Results. In fresh and in greater than or equal to 2 month-old cultures, IFN-gamma strongly stimulated IDO a ctivity, 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 i n cells after 4 days' incubation with IFN-gamma. Staining studies indi cated that the IDO producing cells in synovium were not typical macrop hages. Interferon beta(ser), had weak IDO stimulatory activity that wa s in a few cases additive to that of IFN-gamma. In no case did interfe ron beta(ser) abrogate IFN-gamma induced IDO activity increases. Inter feron alpha 2a also had weak stimulatory activity. Conclusions. IFN-ga mma stimulates IDO production and tryptophan metabolism in cultured hu man synovial cells, and therefore may contribute to this cytokine's in vitro and clinical effects in arthritis and inflammation.