95 Thus, cytokinemediated decreases in available TRP, and therefore 5-HT, may play a role in immune-mediated depression. Indeed, immunotherapy with IL-2 or

IFN-α has been reported to cause significant depletions of TRP which are correlated to the severity of depressive symptoms,96 and depressed patients exhibit lower levels of plasma TRP in association with elevations of IL-6.97 Alternatively, the relevant action of cytokines on monoaminergic systems may be their effect on the 5-HT transporter: IL-1β administration results in increased levels and activity of the 5-HT transporter,98 while IFN-α or IFN-γ increase mRNA for the transporter.99 Such effects would be expected to result Inhibitors,research,lifescience,medical in decreased synaptic 5-HT In MS, increases in proinflammatory cytokines may act via any of these mechanisms to decrease serotonergic neurotransmission and facilitate depression. Inhibitors,research,lifescience,medical Cytokines may alter neurogenesis In the past several years, it has become clear that new neurons are generated throughout the mammalian lifespan in specific brain areas, particularly the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus.100,101 The functional relevance of this adult neurogenesis remains unclear, but a great deal of interest has focused on the possibility Inhibitors,research,lifescience,medical that

impairment of hippocampal neurogenesis plays a role in depression.102 Although the role of the hippocampus in learning and memory is typically emphasized, Inhibitors,research,lifescience,medical the hippocampus is classically considered to be part of the limbic system, and is intimately connected with other brain areas, such as the prefrontal cortex and the amygdala, thought to be involved in Inhibitors,research,lifescience,medical Bax protein depression and regulation of mood. Indeed, subjects with long-standing depression have been shown to have decreases in hippocampal volume.103 Furthermore, both stress and the resulting glucorticoids, which are implicated in depression, reduce hippocampal neurogenesis.104

The precise mechanism by which hippocampal neurogenesis might be impaired in depression is not known, but a variety of evidence suggests that cytokines are involved. Chronic overexpression of IL-6 in transgenic mice results in decreased hippocampal neurogenesis,105 and proinflammatory cytokines released by microglia Thymidine kinase have recently been shown to block hippocampal neurogenesis, with IL-6 being the key regulator of this inhibition.106 Furthermore, IL-6 has been demonstrated to affect the differentiation of newly born cells, biasing cells to develop into glia rather than neurons,106 and IFN-α may act via IL-1 to reduce neurogenesis in the hippocampus.107 Alterations in hippocampal neurogenesis may be particularly relevant in MS, as EAE has been reported to reduce neurogenesis.