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

Tumor necrosis factor is a potent activator of myeloid cells, which acts vi a two cell-surface receptors, the p55 and p75 tumor necrosis factor recepto rs. 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 r ecombinant rat tumor necrosis factor-alpha. Time-related induction of the m essenger RNA encoding c-fos, cyclo-oxygenase-2 enzyme and the inhibitory fa ctor kappa B alpha was assayed as an index of activated neurons and cells o f the microvasculature by intravenous tumor necrosis factor-alpha challenge . The effect of the proinflammatory cytokine on the hypothalamic-pituitary- adrenal axis was determined by measuring the transcriptional activity of co rticotropin-releasing factor and plasma corticosterone levels. Constitutive expression of p55 messenger RNA was detected in the circumventricular orga ns, choroid plexus, leptomeninges, the ependymal lining cells of the ventri cular 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 associate d with a robust activation of the microvasculature. Indeed, intravenous tum or necrosis factor-alpha provoked a rapid and transient transcription of in hibitory factor kappa B alpha and cyclo-oxygenase-2 within cells of the blo od-brain barrier, and a dual-labeling technique provided the anatomical evi dence that the endothelium of the brain capillaries expressed inhibitory fa ctor kappa B alpha. Circulating tumor necrosis factor-alpha also rapidly st imulated c-fos expression in nuclei involved in the autonomic control, incl uding the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus, the central nucleus of the amygdala, the nucleus of th e solitary tract and the ventrolateral medulla. A delayed c-fos mRNA induct ion 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 expres sion of corticotropin-releasing factor primary transcript that was associat ed with a sharp increase in the plasma corticosterone levels 1 h after intr avenous tumor necrosis factor-alpha administration. Taken together, these data provide the evidence that p55 is the most abunda nt tumor necrosis factor receptor in the central nervous system and is expr essed in barrier-associated structures. Circulating tumor necrosis factor h as the ability to directly activate the endothelium of the brain's large bl ood vessels and small capillaries, which may produce soluble molecules (suc h as prostaglandins) to vehicle the signal through parenchymal elements. Th e pattern of c-fos-inducible nuclei suggests complex neuronal circuits soli cited by the cytokine to activate neuroendocrine corticotropin-releasing fa ctor and the corticotroph axis, a key physiological response for the approp riate control of the systemic inflammatory response. (C) 1999 IBRO. Publish ed by Elsevier Science Ltd.