Indoleamine-2, 3-dioxygenase (IDO), an
interferon-γ-inducible
enzyme catalyzing
tryptophan into
kynurenine, exerts dual functions in
infectious diseases, acting as a suppressor of intracellular pathogens and as an immune regulator. We explored the roles of IDO in hepatitis B virus (HBV) clearance from infected patients. We examined IDO activity, serum
chemokines, and
cytokines in 53 HBV-positive patients (25 acute
hepatitis, 14
chronic hepatitis, and 14 hepatic flare) and 14 healthy volunteers. In order to clarify the mechanisms of IDO induction and its impact on HBV replication, we used a culture model consisting of human natural killer cells, plasmacytoid dendritic cells, and HBV-transfected Huh7 cells in which IDO expression is controlled. A robust activation of IDO with an inverse correlation of
alanine aminotransferase at the peak was observed in patients with acute
hepatitis B but not in patients with hepatic flare. In acute
hepatitis patients who eventually cleared HBV, IDO activity,
chemokine (C-X-C motif)
ligand 9 (CXCL9), CXCL10, and CXCL11 increased at the peak of
alanine aminotransferase. In contrast, in patients with hepatic flare, IDO activity remained at lower levels during the observation period, regardless of the surge of CXCL9, CXCL10, and CXCL11 at the
alanine aminotransferase peak. Natural killer cells and plasmacytoid dendritic cells synergistically produced
interferon-γ and
interferon-α, thereby enhancing IDO activity and HBV suppression in Huh7 cells. Such suppressor capacity of IDO on HBV was abrogated in IDO-knockout cells and recovered by the reinduction of IDO in the cells.
CONCLUSION: IDO is an anti-HBV effector and an
indicator of subsequent immune responses operative during the early phase of
infection; its activity is boosted by coexisting natural killer cells and plasmacytoid dendritic cells.