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diffusion, and arc tuned to act locally in an autocrine and paracrine manner. The second problem is that fully functional cytokine receptors are present in the brain (see below) where they mediate the effects of peripherally released or exogenously injected cytokines. For example, blockade of brain TL-1 receptors has been found to abrogate the effects of peripheral immune stimuli on behaviour (Kent, Bluthti, Dantzer, Hardwick, Kelley, Rothwell, & Vannice, 1992a), corticotropin releasing hormone gene expression in the hypothalamus (Kakucska, Qi, Clark, & Lech an, 1993), and body temperature (Klir, McClellan, & Kluger, 1994). The simplest way to interpret these last findings is to assume that cytokines are actively transported into the brain, as proposed for other peptides. For example, insulin has been shown to be able to enter the brain by a receptor-mediated, saturable transport process across brain capillary endothelial cells (Baura, Foster, Porte, Kahn, Bergman, Cobelli, & Schwartz, 1993; Wu, Yang, & Pardridge, 1997). Pharmacokinetic data with radiolabeled cytokines have revealed the existence of specific saturable transport systems for a number of proinflammatory cytokines (Banks, Ortiz, Plotkin, & Kastin, 1991). In the case of insulin, the transporter is nothing else than the insulin receptor. However, the molecular identity of cytokine transporters has not yet been identified. In any case, it is important to point out that the existence of a transport system is not sufficient to explain how peripheral cytokines act on the brain. There is still the problem that in order to be transported, cytokines need to be present in the general blood circulation, or synthesized and released close to their transporter. Furthermore, the intervention of a transport process does not appear to be necessary for peripheral cytokines to enter the brain, since independent experiments have provided evidence for the existence of a brain compartment of cytokines that is inducible by peripheral cytokines (Fig. 3) (Gatti & Bartfai, 1993, Layé, Parnet, Goujon, & Dantzer, 1994).

Brain cells cannot produce cytokines in a coordinated manner in response to peripheral cytokines without a communication pathway for transmission of immune information from the periphery to the brain (Dantzer, 1994). As proposed by Kent et al. (1992b), neural afferents are good candidates for this role, since they already transmit the two sensory components of inflammation, calor and dolor (heat and pain). When LPS or cytokines are injected into the abdominal cavity, an inflammatory response develops locally. The main afferent pathway from the abdominal cavity to the brain is the vagus nerve. The role of the vagus nerve in the transmission of the immune information from the periphery to the brain has first been demonstrated by c-fos mapping experiments. The immediate early gene c-fos is differentially expressed in many regions of the central nervous system following various physiological challenges and can be used as a marker of neuronal activation. Intraperitoneal administration of LPS to rats induced the expression of Fos, the protein product of the c-fos gene, in the primary and secondary projections areas of the vagus nerve. This labeling was completely abrogated by subdiaphragmatic section of the vagus nerve (Wan, Wetmore, Sorensen, Greenberg, & Nance, 1994). Vagotomy also blocked the depressing effects of LPS and IL-lfi on behaviour in rats and mice (Fig. 4) (Bluthé, Walter, Parnet, Layé, Lestage, Verrier, Poole, Stenning, Kelley, & Dantzer, 1994; Bret-Dibat, Bluthé, Kent, Kelley, & Dantzer, 1995).This protecting effect of vagotomy was not due to an impaired peripheral immune response since the increase in the levels of IL-lfJ that was induced in the peritoneal macrophages and plasma in response to an intraperitoneal injection of LPS was not impaired by vagotomy (Bluthé et al., 1994; Layé, Bluthé, Kent, Combe, Médina, Parnet, Kelley, & Dantzer, 1995). The involvement of the vagus nerve in the behavioural effects of cytokines is specific to cytokines that are released in the

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