Systemic interleukin-1 induces early and late patterns of c-fos mRNA expression in brain

Abstract

This study was designed to examine the mechanisms by which systemic interleukin-1 affects neuroendocrine systems in the brain. Intraperitoneal injections of interleukin-1 beta (1.25 micrograms/rat) were administered to rats. One or three hours after injection, the expression levels of the immediate-early gene c-fos and of genes for several neuropeptides, receptors, and enzymes were examined by in situ hybridization histochemistry. In the brainstem at 1 hr, c-fos mRNA was elevated in the area postrema and nucleus of the solitary tract, but not in the locus coeruleus. At 3 hr, the c-fos mRNA levels had increased further in the nucleus of the solitary tract. Rostrally, elevations in c-fos mRNA levels were found in the hypothalamic and thalamic paraventricular nuclei, central nucleus of amygdala, bed nucleus of the stria terminalis, and medial preoptic area, peaking at 1 hr and diminishing at 3 hr. In addition, at 3 hr a new pattern of c-fos activity emerged--the arcuate nucleus and cells at the external margins throughout the brain now expressed c-fos mRNA. Corticotropin-releasing hormone mRNA levels were doubled in the paraventricular nucleus at 1 and 3 hr, concomitant with elevations in plasma adrenocorticotrophic hormone (ACTH) and corticosterone. Tyrosine hydroxylase mRNA levels in the brainstem did not change. The c-fos mRNA induction patterns reveal a temporally dynamic response to interleukin-1 administration. We propose that the early set of structures responding to interleukin-1 initiates the neuroendocrine response to cytokines. Coactivation of the area postrema and nucleus of the solitary tract may reflect entry into the brain and neural transduction of the peripheral signal. The late set--including the nucleus of the solitary tract, arcuate nucleus, and the brain's edge--may reflect cellular activation along the diffusion routes traveled by interleukin-1 or a bioactive transduction product, because the pattern of edge labeling is similar to the autoradiographic pattern of flow lf radiolabeled tracer substances in the cerebrospinal fluid. The late c-fos mRNA response to interleukin-1, therefore, may represent a demonstration of information transfer in the parasynaptic mode, also known as volume transmission.

Cytokine signals propagate through the brain

“…Volume transmission and neuronal projections were previously proposed to mediate cytokine effects in and around the BBB. 54 The evidence reviewed here extends this proposal to cytokine signal propagation throughout the brain.…”

“…46 In contrast to the rather limited activation around blood vessels making up the BBB, a more important spread of cellular activation occurs away from circumventricular organs (CVOs) and invades the adjacent parenchyma over time in response to peripheral injection of IL-1␤ or LPS. 46,54,55 The blood vessels in CVOs lack a functional BBB. Therefore, molecules up to 500 kDa, including IL-1, can be found in these organs after iv injection.…”

Inactivation of the Cerebral NFκB Pathway Inhibits Interleukin-1β-Induced Sickness Behavior and c-Fos Expression in Various Brain Nuclei

“…or i.v. injection of IL-1b (Brady et al, 1994;Day and Akil, 1996;Ericsson et al, 1994;Herkenham et al, 1998). The preoptic area has also been reported to be activated (Brady et al, 1994), although this was not the case, at 1 h, in the present study.…”

“…injection of IL-1b (Brady et al, 1994;Day and Akil, 1996;Ericsson et al, 1994;Herkenham et al, 1998). The preoptic area has also been reported to be activated (Brady et al, 1994), although this was not the case, at 1 h, in the present study. In terms of mechanisms, c-Fos activation of these various brain structures is assumed to be mediated neurally since it maps the primary and secondary projection areas of the vagus nerves (Konsman and Cartmell, 1997;Konsman et al, 2000a) and is abrogated by section of the vagus nerves under the diaphragm (Konsman et al, 2000a;Konsman and Dantzer, 2001).…”

Effects of cytokines and infections on brain neurochemistry

“…Increases in Fos are also commonly observed in the central amygdaloid nucleus, the medial preoptic area, the bed nucleus of the stria terminalis, and the NTS. mRNA for Fos (c-fos) is also induced in most of the same structures [57][58][59]. The Fos response to IL-1 appears to depend on activation of the PVN by noradrenergic neurons because it is markedly attenuated in mice depleted of NE with 6-hydroxydopamine (6-OHDA) [60].…”