The afferent signalling of fever.

When infectious micro-organisms invade the body, fever often ensues. It is the most familiar and most manifest sign of infection. Yet, despite its ubiquity, little is definitively known regarding the detailed mechanism of its induction. The generally prevalent view is that entry into the body of such infectious micro-organisms first activates innate immune responses, which include the release of a complex variety of soluble mediators. Among these, the cytokines tumour necrosis factor (TNF) alpha, interleukin (IL)-1beta and IL-6 are thought to convey the pyrogenic message to the brain region where fever is regulated, namely the preoptic area (POA) of the anterior hypothalamus. The mechanism by which these peripheral signals may be transduced into central nervous signals is currently a matter of lively controversy. The issue is not trivial because, to the extent that these relatively large, hydrophilic peptides may be released into the circulatory system and transported to the brain by the bloodstream, they have to pass through the blood-brain barrier (BBB), which is impermeable to them. At least two routes are possible, and there is evidence for both: (1) active transport across the BBB by cytokine-specific carriers, and (2) message transfer where the BBB is 'leaky', i.e. in the 'sensory' circumventricular organs, particularly the organum vasculosum laminae terminalis (OVLT), on the midline of the POA, by the presumptive activation by, an as yet, indeterminate means of neurons projecting into the OVLT from the brain. But alternative pathways are also possible and support for some has been obtained: (1) the circulating cytokine-induced generation of BBB-permeable prostaglandin E2, the most proximal, putative mediator of fever, by endothelial cells of the cerebral microvasculature or perivascular microglia and meningeal macrophages, and (2) direct transmission to the POA of the pyrogenic messages via peripheral (largely vagal) afferent nerves activated by the cytokines. However, all four of these mechanisms have shortcomings (Blatteis & Sehic, 1997).

Interleukin-1 inhibits NMDA-stimulated GnRH secretion: associated effects on the release of hypothalamic inhibitory amino acid neurotransmitters.

Immune system activation is often accompanied by alterations in the reproductive axis. Interleukin-1 (IL-1), a polypeptide cytokine, has been postulated as a chemical messenger between the immune and the neuroendocrine systems. Using superfused hypothalamic fragments explanted from intact male rats, we evaluated the effects of IL-1 (0. 5 and 5 nM) on basal and N-methyl-D-aspartate (NMDA)-stimulated release of gonadotropin-releasing hormone (GnRH), and the associated modifications in the output of inhibitory amino acid neurotransmitters involved in the control of GnRH secretion. IL-1 did not modify basal GnRH release, but markedly restrained the stimulatory effect of NMDA on GnRH secretion. gamma-Aminobutyric acid, glycine and taurine concentrations significantly increased in the superfusion medium only after pretreatment with the higher dose of IL-1 (p < 0.05). Our results indicate that this cytokine inhibits NMDA- stimulated GnRH release, affecting the activity and/or the release of hypothalamic excitatory and inhibitory amino acid neurotransmitters participating in the regulation of GnRH secretion.

Immunocytochemical localization of sGnRH and cGnRH-II in the brain of goldfish, Carassius auratus.

The immunocytochemical distribution of salmon gonadotropin-releasing hormone (sGnRH) and chicken GnRH-II (cGnRH-II) neurons in the brain of goldfish was examined using respective antisera. Salmon GnRH-immunoreactive (ir) cell bodies were localized in the area between the olfactory nerve and the olfactory bulb (the terminal nerve ganglion), the ventral telencephalon, the preoptic area, and the hypothalamus. Chicken GnRH-II-ir cell bodies were observed in the same areas as were those of sGnRH, although the number of cell bodies were fewer than those of sGnRH. In addition, chicken GnRH-II-ir cell bodies were also observed in the midbrain tegmentum where no sGnRH-ir cell bodies were found. Both sGnRH-ir and cGnRH-II-ir fibers were distributed not only in the hypothalamus and the pituitary gland but also in various brain areas from the olfactory bulb to the spinal cord. The wide distribution of GnRH-ir fibers suggests that in the goldfish, sGnRH and cGnRH-II not only regulate gonadotropin release from the pituitary gland but also function as neuromodulators in various brain regions.

Hypothalamic modulation of splenic natural killer cell activity in rats.

1. The cytotoxic activity of splenic natural killer cells measured by a standard chromium release assay in urethane and alpha-chloralose-anaesthetized rats was significantly suppressed 20 min after bilateral ablation of the medial part of the preoptic hypothalamus (MPO). The suppression was completely blocked by prior splenic denervation. The splenic natural killer cell activity of MPO sham-lesioned rats or thalamus-lesioned rats, both having an intact splenic innervation, were not different from that of a non-treated control group. 2. Electrical stimulation of the bilateral MPO (0.1 ms, 0.1-0.3 mA, 5-100 Hz) suppressed the efferent activity of the splenic nerve in all six rats examined. The reduction of the nerve activity was accompanied by a transient fall in blood pressure. An I.V. injection of phenylephrine (3 micrograms/0.3 ml) also evoked a suppression of the nerve activity, which was accompanied by transient hypertension, suggesting that the suppressive effect of the MPO stimulation was independent of changes in blood pressure. On the other hand, a bilateral lesion of the MPO resulted in a sustained increase in the electrical activity of the splenic sympathetic nerve filaments which lasted for more than 2 h. 3. Microinjection of monosodium-L-glutamate (0.1 and 0.01 M in 0.1 microliters saline) unilaterally into the MPO evoked a transient suppression of the efferent discharge rate of the splenic nerve activity within 1 min, which was also accompanied by a decrease in blood pressure. The injection of saline (0.1 microliter) into the MPO had no effect. The microinjection of recombinant human interferon-alpha (200 and 2000 U in 0.1 microliter saline) into the MPO dose dependently increased the splenic nerve activity without any change in blood pressure. 4. In contrast, microinjection of interferon-alpha into the paraventricular nucleus of the hypothalamus (PVN) had no effect on splenic nerve activity, although an injection of glutamate increased the nerve activity. 5. The present results, taken together with previous reports, suggest that the neuronal networks between the MPO and the splenic sympathetic nerve, which may be activated by centrally administered interferon-alpha, are important in the suppression of the splenic cellular immunity.

Nuclear localization of estrogen receptor-immunoreactivity in the preoptic area of female rats and its reduction by intraventricular colchicine treatment.

The subcellular localization of estrogen receptor (ER) was investigated in the preoptic area of ovariectomized female rats by electron microscopic immunohistochemistry, using a monoclonal antibody to ER. ER-immunoreactivity was localized in the nuclei of neurons of the periventricular preoptic nucleus (Pe) and the medial preoptic area (MPA). ER-immunoreactivity had a speckled pattern in the nucleus, but was not observed in the nucleolus or cytoplasm. After intraventricular colchicine treatment, ER-immunoreactivity within the nucleus was reduced drastically in neurons of the Pe and the MPA. The possible mechanism by which colchicine alters ER-immunoreactivity is mentioned.