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Figure 6, RT-PCR demonstration of the expression of type I and type II IJ.-l receptors in the pituitary, hippocampus and liypothalamus of mice and its regulation by systemic administration of LPS. Mice were killed either before or at different times after ip injection of LPS (lOpg/mouse) and total RNA was extracted from various tissues and brain structures for RT-PCR analysis. Yeast lotal RNA served as a negative control. The left portion of the figure represents a typical acrylamide gel showing transcripts for the type 1 IL-1 receptor (702 bp) and the type II IL-1 receptor (297 bp). Tin: right porlion of the figure represents variations of 1L-! receptor thRNA in the hypothalamus and hippocampus (expressed as percent of beia2-microglobuiin mRNA, mean of 3 experiments) in response to ip LPS.

Fos immunohistochemistry, they found that Fos was induced in CI noradrenergic neurons in the ventrolateral medulla, lliese neurons project to the CRH containing neurons of the paraventricular nucleus of the hypothalamus (PVN). Interruption of the input from the CI cells to the PVN by knife cuts prevented the CRH response to IL-tp. In the case of fever, Saper and colleagues (Elmquist, Scammel, & Saper, 1997) observed that intravenously injected LPS activated Fos in the ventromedial preoptic area of the hypothalamus (VMPO), Using retrograde tracing, they found that the VMPO has both direct and indirect (via the anterior perifornical area and parastrial nucleus) projections to the autonomic parvicellular divisions of the PVN. They proposed that activation of VMPO efferents following LPS disinhibit PVN neurons that are involved in thermogenesis by inhibition of warm sensitive neurons that are located in the anterior perifornical area, therefore raising the thermostatic set-point for thermoregulation (Elmquist ct al., 1997). In the case or food intake, Plata-Salaman and colleagues (Piata-Salaman, Oomura, & Kai, 1988) showed that IL-1 (3 suppressed the neuronal activity of the glucose-sensitive neurons in the lateral hypothalamic area, while activating glucose-sensitive neurons in the hypothalamic ventromedial nucleus. However, the evidence for a direct involvement of these hypothalamic neural structures in the anorexia induced by immune stimuli is still lacking.

Whether cytokines directly act on the above described neural pathways or activate them via intermediates such as prostaglandins and NO is still a matter of controversy. There is no doubt that cytokines are powerful inducers of the expression of cyclooxygenase-2 (COX-2) (Breder & Saper, 1996; Cao, Matsumura, Yamagata, & Watanabe, 1996) in the brain. COX-2 is the rate limiting enzyme in the conversion of arachidonic acid to prostanoids. This enzyme is induced in brain vascular- and perivas-cular-associated cells in response to systemic administration of LPS and IL-1|J, but not IL-6 (Lacroix and Rivest, 1998). Cytokines also induce NO synthase in the brain (Wong, Rettori, Al-Shekhlee, Bongiorno, Canteros, McCann, Gold, & Licinio, 1996). The inducible form of NO synthase (iNOS), also called type II NOS, is synthesised by macrophages in response to inflammatory stimuli. Using in situ hybridization, Wong et al. (1996) reported that there is no detectable expression of iNOS in the brain in basal conditions, but that this enzyme is rapidly induced in vascular, glial, and neuronal structures of the rat brain in response to IP LPS. The induction of this enzyme in the hypothalamus was confirmed by Satta and colleagues (Satta, Jacobs, Kaltsas, & Grossman, 1998), using RT-PCR.

Since many of the functional neuroanatomical studies on the brain effects of immune stimuli were carried out using the intravenous route, and endothelial cells of the brain microvasculature respond to intraluminar cytokines by producing prostaglandins, Elmquist et al. (1997) proposed that these intermediates mediate the CRH and fever responses to immune stimuli. These actions of prostaglandins would take place in different regions of the brain, the CI noradrenergic neurons for the CRH reponse, and the VMPO neurons in the case of fever. Stimulation of COX-2 in the brain microvasculature of the MPOA results in an increased local production of prostaglandins. These intermediates would bind to specific receptors expressed on nearby neurons to promote the fever in response to peripheral immune stimuli (Elmquist et al., 1997; Lacroix & Rivest, 1998). In the case of a local inflammation, prostaglandins released at the site of inflammation would activate local sensory fibers, resulting in the transmission of the peripheral immune message to the brain. The way activation of vagal sensory fibers and brain production of IL-ip combine with each other to allow the development of the host response to infection has been examined by Konsman and colleagues (Konsman, Kelley, & Dantzer, 1998), using immunohisto-chemistry for Fos and IL-1(3, and in situ hybridization for the expression of iNOS mRNA, taken as a marker of IL-1[3 bioactivity. In this study, rats were killed at different times after IP LPS. IL-l(3-positive cells were found 2h after LPS in circum-ventricular organs and the choroid plexus.The cells that expressed IL-1J3 were isolectin-positive cells and their shape allowed to identify them as perivascular phagocytic cells. Fos expression was restricted at that time to brain parenchymal structures such as the nucleus tractus solitarius, medial preoptic area, paraventicular nucleus, supraoptic nucleus, and central amygdala. Eight hours after LPS, Fos became apparent in cir-cumventricular organs. This was associated with a shift of expression of IL-ip from circumventricular organs to adjacent brain structures such as the nucleus tractus solitarius and medial preoptic area. Since this was accompanied by an expression of iNOS at the interface between circumventricular organs and adjacent brain nuclei, these results were interpreted as suggesting that IL-ip functions as a volume transmisión signal, which originates from perivascular ceils ai the blood side of the circumvcntric-ular organs, is passively conveyed through the inlerstitmm of circum ventricular organs by pulsations of nearby arterioles, and acts on microglial cells that are located on the neural side of the circumventricular organs. From there, the IL-lp message would propagate itself throughout the brain parenchyma by recruiting adjacent microglial cells (Konsman et ai., 1998) (Fig. 7). it is important to note thai a similar picture was obtained by Quan and colleagues (Quail, Whiteside, Kim, & Herkenham, 1997), based on the induction of IkBcc expression in the brain in response to LPS. IkB is a cytoplasmic protein that binds to the nuclear transcription factor NFkB, preventing its translocation to the nucleus. Upon cellular activation by immune signals, IkB is

Figure 7. Schematic drawing of) he nay !L-l[i is synthesized in ihe brain in response to ip LPS and its mechanisms of action. The upper portion of the figure represents a sagittal section of the rat brain whereas the lower left hand portion of the figure represents a coronal section of (he brain at the level of the area postrcma (AP). The lower right hand of the figure represents the liver. Intraperitoneal^ administered LPS induces the release of IL-l|i by Kupifer cells in the liver, resulting in the activation of vagal afferent*. This neural message is transmitted to the NTS. and from there to the parabnichial nuclei (PB). the ventrolateral medulla (VLM). and the fore brain nuclei thai are implicated in Ihe metabolic, neuroendocrine and behavioral components of the systemic host response to infection (Medial Preoptic area, MPO; Paraventricular Nucleus, PVN; Supraoptic Nucleus of the hypothalamus, SON; Central nucleus of the Amygdala, CeA; Bed nucleus of the Stria Terminalis. BST). Neural activation of these structures is apparent from Fos expression. 1 L I (i. represented by asteriks, is first synthesized and released in the circum ventricular organs (Orgamim Vasculosum of the Lamina Terminalis, OVLT; Area Postrcma. AP; Subfornical Organ, SF'O: Median Eminence, ME) and the choroid plexus (ChP). In ihe AP. IL-l|i is synthesized and released by perivascular phagocytic cells and then diffuses throughout the interslitium to act on 1L-1 type I receptors that are present on AP neurons and project to the Nucleus Tract us Sohtanu.s (NTS). This results in a second wave of FOS expression in the NTS and its projection structures. 'Itie NTS plays therefore a pivotal role in the integration of peripheral and central IL-lp. A second wave of IL-1 |i expression occurs on the neural side of the btood-bram barrier and corresponds to the sequential activation of ramified microglial cells. Not represented in this figure is Ihe fact that the actions of iL-l[5 on many of its target structures are mediated by intermediates such as prostaglandins and NO (From Konsman et at. 1999).

phosphorylated and dissociates itself from NFkB. NFkB is then able to enter the nucleus and stimulate transcription of a wide array of genes, including those responsible for COX-2 and iNOS. Since activation of NFkB is followed by induction of IkB, the detection of IkB induction in the brain reveals the extent and cellular location of brain-derived immune molecules in response to peripheral immune stimuli. In response to IP LPS, IkB mRNA was first expressed in cells lining the blood side of the blood-brain barrier and progressed to glial cells inside the brain (Quan et al., 1997).

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