The role of vagal afferents is more important for the behavioral depression that develops in response to peripheral immune stimuli than for the induction of fever and activation of the HPA axis.78 De novo synthesis by BBB cells The fourth pathway is that peripheral immune stimuli may induce the production of cytokines by cells of the BBB, which then secret cytokines into the Inhibitors,research,lifescience,medical brain parenchyma. In situ hybridization studies showed that the cells of the BBB respond to peripheral immune stimulation by producing IL-1,79 IL-6,80 and TNF-α.81 Thus, during systemic immune challenge, production

of cytokines by cells of the BBB may result in widespread cytokine activity in the entire CNS. This is consistent with a report that the IL-1 bioactivity can be found in all brain regions after high-dose peripheral LPS injection.82 Local action of cytokines Inhibitors,research,lifescience,medical at many brain sites may actually be mediated via the receptors on endothelial cells. This binding induces another important effect of peripheral cytokines on cells of the BBB: the induction Inhibitors,research,lifescience,medical of cyclooxygenase-2 (COX-2), a rate-limiting enzyme of prostaglandin synthesis. Predominantly IL-1 and TNF-α induce the expression of COX-2 in endothelial cells of the BBB.83,84 As many cytokine-induced CNS effects can be blocked

by COX inhibitors,85,86 the cytokine-induced COX-2 activity in BBB cells may represent a central mechanism Inhibitors,research,lifescience,medical of cytokine-CNS interaction. Infiltrating leukocytes Finally, it has to be considered that cytokines may enter the brain via infiltrating leukocytes. It has long been known that leukocytes may enter the brain under both normal and pathological conditions.87 In normal brain, scattered and random crossing of the BBB by leukocytes provide immune surveillance

for the CNS.88 Under pathological conditions such as bacterial meningitis, Inhibitors,research,lifescience,medical activated leukocytes expressing 2-MeOE2 concentration inflammatory cytokines may infiltrate the brain.89,90 Additionally, CNS action of cytokines may weaken the BBB, promoting an increased infiltration of cytokine producing leukocytes. Summary The above mechanisms for the entrance of cytokines into the brain highlight the second limitations of measuring peripheral levels of cytokines in neuropsychiatrie disorders. Cytokine levels in the blood (ie, serum or plasma) may reflect the systemic immune status and have been established as useful clinical markers in septic shock, inflammatory disorders, or cancers,91 but cannot conclusively clarify the cytokine expression within the CNS. Cytokine and cytokine receptor expression in the brain The specificity of the response to cytokines is provided by their receptors. Thus the expression of cytokine receptors is necessary for signal transmission of the cytokines entering the brain. Table 1 lists some selected cytokines and their receptors that are expressed within the CNS. Table I Expression of some selected cytokines and their receptors on neurons and glial cells.