DIFFERENTIAL REGULATION OF INDOLEAMINE 2,3-DIOXYGENASE EXPRESSION BY NITRIC-OXIDE AND INFLAMMATORY MEDIATORS IN IFN-GAMMA-ACTIVATED MURINE MACROPHAGES AND MICROGLIAL CELLS

Induction of indoleamine 2,3-dioxygenase (IDO) and nitric oxide syntha se (NOS) is involved in the immunomodulatory roles of lFN-gamma and ev idence suggests that these pathways are functionally cross-regulated. We report here that nitric oxide (NO) negatively modulates the express ion of IDO activity in IFN-gamma-primed macrophages, but not in microg lial cells from mouse, In MT2 macrophages, the induction of IDO activi ty by IFN-gamma was further increased by the presence of NOS inhibitor s, whereas culturing of IFN-gamma-activated MT2 cells with NO generato rs produced a marked reduction of IDO activity expression, Conversely, neither NOS inhibitors nor exogenous NO affected the induction of the enzyme activity in N11 microglial cells after IFN-gamma activation, L PS and picolinic acid, two costimulatory agents that up-regulate induc ible NOS in activated cells, regulated IDO induction differently in th e two cell lines. LPS and picolinic acid caused a significant decrease of IDO activity in IFN-gamma-activated MT2 cells, This effect, howeve r, did not appear to be mediated by the ability of LPS and picolinic a cid to stimulate NO production. In N11 cells, LPS further stimulated t he enzyme activity and picolinic acid had no effect. Northern blot ana lysis revealed that, in MT2 macrophages, NOS inhibitors increased the levels of IDO mRNA, while a reduction was observed with picolinic acid , No changes in IDO mRNA levels were detected in N11 cells, Consistent with the functional heterogeneity of phagocytes, the reported results indicate the existence of marked differences in the regulation of IDO expression between murine macrophages and microglial cells.