Elsevier

Neuroscience

Volume 93, Issue 4, August 1999, Pages 1449-1464
Neuroscience

Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood–brain barrier

https://doi.org/10.1016/S0306-4522(99)00225-0Get rights and content

Abstract

Tumor necrosis factor is a potent activator of myeloid cells, which acts via two cell-surface receptors, the p55 and p75 tumor necrosis factor receptors. The present study describes the cellular distribution of both receptor messenger RNAs across the rat brain under basal conditions and in response to systemic injection with the bacterial endotoxin lipopolysaccharide and recombinant rat tumor necrosis factor-α. Time-related induction of the messenger RNA encoding c-fos, cyclo-oxygenase-2 enzyme and the inhibitory factor kappa B alpha was assayed as an index of activated neurons and cells of the microvasculature by intravenous tumor necrosis factor-α challenge. The effect of the proinflammatory cytokine on the hypothalamic–pituitary–adrenal axis was determined by measuring the transcriptional activity of corticotropin-releasing factor and plasma corticosterone levels. Constitutive expression of p55 messenger RNA was detected in the circumventricular organs, choroid plexus, leptomeninges, the ependymal lining cells of the ventricular walls and along the blood vessels, whereas p75 transcript was barely detectable in the brain under basal conditions. Immunogenic insults caused up-regulation of both tumor necrosis factor receptors in barrier-associated structures, as well as over the blood vessels, an event that was associated with a robust activation of the microvasculature. Indeed, intravenous tumor necrosis factor-α provoked a rapid and transient transcription of inhibitory factor kappa B alpha and cyclo-oxygenase-2 within cells of the blood–brain barrier, and a dual-labeling technique provided the anatomical evidence that the endothelium of the brain capillaries expressed inhibitory factor kappa B alpha. Circulating tumor necrosis factor-α also rapidly stimulated c-fos expression in nuclei involved in the autonomic control, including the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus, the central nucleus of the amygdala, the nucleus of the solitary tract and the ventrolateral medulla. A delayed c-fos mRNA induction was detected in the circumventricular organs, organum vascularis of the lamina terminalis, the subfornical organ, the median eminence and the area postrema. The paraventricular nucleus of the hypothalamus exhibited expression of corticotropin-releasing factor primary transcript that was associated with a sharp increase in the plasma corticosterone levels 1 h after intravenous tumor necrosis factor-α administration.

Taken together, these data provide the evidence that p55 is the most abundant tumor necrosis factor receptor in the central nervous system and is expressed in barrier-associated structures. Circulating tumor necrosis factor has the ability to directly activate the endothelium of the brain's large blood vessels and small capillaries, which may produce soluble molecules (such as prostaglandins) to vehicle the signal through parenchymal elements. The pattern of c-fos-inducible nuclei suggests complex neuronal circuits solicited by the cytokine to activate neuroendocrine corticotropin-releasing factor and the corticotroph axis, a key physiological response for the appropriate control of the systemic inflammatory response.

Section snippets

Animals and immunogenic stimuli

Adult male Sprague–Dawley rats (Charles River Canada, St Constant, Québec, Canada; ∼240–275 g) were acclimated to standard laboratory conditions (14-h light/10-h dark cycle; lights on at 06.00 and off at 20.00), with free access to rat chow and water. All efforts were made to minimize animal suffering and to reduce the number of rats used, and all protocols were approved by the Laval University Animal Welfare Committee. A total of 87 rats was assigned to different protocols divided among the

Basal expression of p55 and p75 receptor messenger RNAs

Figure 1 shows representative examples of the rostrocaudal distribution of the gene encoding the TNF-α p55 receptor in the rat brain. Low hybridization signal was detected in non-parenchymal barrier-related structures, such as the ependymal lining cells of the intracerebroventricular wall, the leptomeninges, the choroid plexus and along the blood vessels. The ME/arcuate nucleus, the PVN, the supraoptic nucleus (SON), the AP and the pyramidal layer of the cerebellar cortex exhibited positive p55

Discussion

The present study provides the fine distribution of the genes encoding p55 and p75 in the rat brain under basal conditions and following systemic injections with the bacterial endotoxin LPS and the exogenous ligand for these TNF receptors. Both p55 and p75 mRNAs were visible in unchallenged brains, but the TNF p55 receptor was clearly the most abundant; convincing hybridization signal was detected in the choroid plexus, leptomeninges, ependymal lining cells of the ventricular walls, PVN, SON,

Conclusions

Bebo and Linthicum3 have recently reported that interferon-γ and IL-1β up-regulated the levels of both p55 and p75 TNF receptor mRNAs in mouse cerebrovascular endothelium, while TNF-α had no effect. This latter study was, however, performed using cerebrovascular endothelial cells cultured from experimental autoimmune encephalomyelitis-susceptible (SJL/J) and experimental autoimmune encephalomyelitis-resistant (Balb/c) mice. Our in vivo experiments in conscious and freely moving male rats show a

Acknowledgements

This research was supported by the Medical Research Council of Canada (MRCC). Sylvain Nadeau holds a Studentship from the MRCC and Serge Rivest is an MRCC Scientist. We thank Dr I. Verma (The Salk Institute, La Jolla, CA, U.S.A.) for the generous gift of the rat c-fos cDNA, Dr A. Israel (Institut Pasteur, Paris, France) for the mouse IκB-α cDNA, Dr S. Watson (The University of Michigan, Ann Arbor, MI, U.S.A.) for the pGEM3 plasmid containing a pure CRF intronic piece, Dr Adolf Himmler (Bender &

References (43)

  • L.A Tartaglia et al.

    A novel domain within the 55 kd TNF receptor signals cell death

    Cell

    (1993)
  • L.A Tartaglia et al.

    Two TNF receptors

    Immun. Today

    (1992)
  • M.J VanderMeer et al.

    Effects of cytokines on pituitary beta-endorphin and adrenal corticosterone release in vitro

    Cytokine

    (1996)
  • S Akira et al.

    Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF)

    Fedn Proc. Fedn Am. Socs exp. Biol.

    (1990)
  • J Andersson et al.

    Bacterial toxin-induced cytokine production studied at the single-cell level

    Immun. Rev.

    (1992)
  • M.H Bemelmans et al.

    LPS-induced sTNF-receptor release in vivo in a murine model. Investigation of the role of tumor necrosis factor, IL-1, leukemia inhibiting factor, and IFN-gamma

    J. Immun.

    (1993)
  • R Bernardini et al.

    Interactions between tumor necrosis factor-α, hypothalamic corticotropin-releasing hormone, and adrenocorticotropin secretion in the rat

    Endocrinology

    (1990)
  • B Beutler et al.

    The biology of cachectin/TNF-α primary mediator of the host response

    A. Rev. Immun.

    (1989)
  • L Brady et al.

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

    J. Neurosci.

    (1994)
  • L.J Crofford et al.

    Involvement of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression by interleukin-1 in rheumatoid synoviocytes

    Arth. Rheum.

    (1997)
  • A Ericsson et al.

    A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons

    J. Neurosci.

    (1994)
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