Endothelial activation is an intermediate step for peripheral lipopolysaccharide induced activation of paraventricular nucleus.
Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) activates the paraventricular nuclei of the hypothalamus (PVN), and consequently the hypothalamus-pituitary adrenal axis. Inflammatory cytokine interleukin-1 (IL-1) has been considered as a key mediator that translates the peripheral LPS stimulation into neuronal activation in the PVN. Several studies attempting to localize the expression of receptors for IL-1 (IL-1R), however, have failed to detect IL-1R on PVN neurons. It remains unclear, therefore, how IL-1 might stimulate the neurons of the PVN. In this study, we traced the cellular responsiveness to IL-1 by measuring the mRNA production of the cytokine responsive gene IkappaBalpha in the PVN. After either peripheral injection LPS or intracerebroventricular (i.c.v.) injection of IL-1beta, IkappaBalpha mRNA was found mostly in endothelial cells of the brain with the highest level of expression in PVN blood vessels. In addition, both injections also induced the expression of cyclooxygenase-2 in brain endothelial cells. Pretreatment with indomethacin, a cyclooxygenase inhibitor, blocked LPS and IL-1 induced neuronal activation in the PVN, but did not reduce the induction of IkappaBalpha in PVN endothelium. These results show that IL-1 acting on the endothelial cells of the brain, particularly in the PVN, may be an intermediate step relating peripheral immune signals to the brain.
Quan
Ning
N
Department of Oral Biology, Health Science Center, Ohio State University, Columbus, OH 43210, USA. quan.14@osu.edu
He
Lingli
L
Lai
Wenmin
W
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D020672:I-kappa B Proteins / Q000235:genetics; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D010286:Paraventricular Hypothalamic Nucleus / Q000098:blood supply* / Q000187:drug effects* / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; C000606206:Nfkbia protein, rat; D016760:Proto-Oncogene Proteins c-fos; D000072000:NF-KappaB Inhibitor alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin