Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse

Accumulation of quinolinic acid and neuroactive kynurenines derived from tryptophan are of potential significance in human neuropathologic diseases because of their neurotoxic and convulsant properties. Clinical studies have established that sustained elevations of quinolinic acid, l-kynurenine and kynurenic acid within the cerebrospinal fluid occur in patients with a broad spectrum of inflammatory diseases and correlate with markers of immune activation and interferon-y activity. The present study describes an animal model that replicates these clinical observations and investigates the role of interferon-γ as a mediator between immune activation and increased kynurenine pathway metabolism. Marked elevations in quinolinic acid, l-kynurenine and 3-hydroxykynurenine as well as an increased ratio of quinolinic acid: kynurenic acid in brain occurred 24 h after systemic pokeweed mitogen administration to C57BL6 mice. In plasma, l-tryptophan and kynurenic acid levels were reduced by pokeweed mitogen, while the concentrations of l-kynurenine, 3-hydroxykynurenine and quinolinic acid were increased. Interferon-γ, pokeweed mitogen and lipopolysaccharide induced indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway and increased both l-kynurenine and quinolinic acid concentrations of brain and systemic tissues, particularly in the lung, gastrointestinal tract and spleen. In contrast, hepatic tryptophan-2,3-dioxygenase activity was either reduced or unaffected. Increases in kynurenine pathway metabolism were sustained in mice given daily injections of interferon-γ for seven days and subsequent responses to interferon-γ were further enhanced. In contrast, daily administration of lipopolysaccharide was associated with subsequent attenuated responsiveness (tolerance) to lipopolysaccharide, pokeweed mitogen and interferon-γ. Systemic administration of a monoclonal antibody to mouse interferon-γ either attenuated or abolished the responses of kynurenine pathway metabolism to pokeweed mitogen and interferon-γ. We conclude that acute and chronic increases in quinolinic acid and neuroactive kynurenines follow immune stimulation in mice and result from indoleamine-2,3-dioxygenase induction. The results demonstrate that interferon-γ is an important mediator between immune stimulation and indoleamine-2,3-dioxygenase induction. These increases in kynurenine pathway metabolism closely parallel the responses documented in patients with a broad spectrum of inflammatory diseases. Mice treated with immune stimuli are a useful model to investigate the relationships between immune activation and kynurenine pathway metabolism.