title: Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain.
abstract: Expression of the inhibitory factor kappaB alpha (IkappaB alpha) reflects the activity of nuclear factor kappaB(NF-kappaB) and is a powerful tool to investigate the regulation of the transcription factor within the CNS. IkappaB alpha mRNA was evaluated in the rat brain by means of in situ hybridization following different immunogenic stimuli; i.e., intraperitoneal (i.p.) and intravenous (i.v.) lipopolysaccharide (LPS), i.v. recombinant rat interleukin (IL) 1beta, IL-6, or tumor necrosis factor-alpha (TNF-alpha), and intramuscular (i.m.) turpentine injection, used here as a model of systemic localized inflammatory insult. Systemic LPS, IL-1beta, and TNF-alpha caused a rapid and transient transcriptional activation of IkappaB alpha along the blood vessels of the entire brain; the signal was very intense 30-60 min after the i.v. injections and returned to undetectable levels from 2 to 12 h depending on the challenge. Double-labeling procedure provided the anatomical evidence that IkappaB alpha-expressing cells within the microvasculature were essentially of the endothelial type, as they were immunoreactive to the von Willebrand factor. Scattered small cells were also found across the brain of LPS-, IL-1beta-, and TNF-alpha-injected rats at time 1-3 h, and microglial (OX-42)-immunoreactive cells were positive for the transcript. Such expression within parenchymal microglia was nevertheless not observed in the brain following a localized and sterile inflammatory insult. Indeed, i.m. turpentine administration stimulated IkappaB alpha transcription quite uniquely within the endothelium of the brain capillaries, an effect that paralleled the swelling of the injection site and lasted up to 24 h after the aggression. In contrast to these immunogenic challenges, i.v. IL-6 injection failed to activate the gene encoding IkappaB alpha in the rat brain. These results indicate that NF-kappaB may play a crucial role in specific cellular populations of the CNS to trigger transcription of immune-related genes and that IkappaB alpha resynthesis may act as a dynamic intracellular inhibitory feedback to avoid exaggeration of the response. It is possible that IkappaB alpha expression in cells of the blood-brain barrier is a general mechanism that takes place during systemic inflammation, whereas the participation of NF-kappaB-related molecules within parenchymal cells of the CNS is solicited during more severe conditions such as blood sepsis and endotoxemia.
authors.affiliation: Laboratory of Molecular Endocrinology, CHUL Research Center and Laval University, Sainte-Foy, Quebec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Laflamme
authors.forename: S
authors.initials: S
authors.lastname: Rivest
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D016207:Cytokines / Q000097:blood*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004731:Endotoxins / Q000494:pharmacology; D015870:Gene Expression; D007031:Hypothalamus / Q000378:metabolism; D020672:I-kappa B Proteins; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D016207:Cytokines; D004268:DNA-Binding Proteins; D004731:Endotoxins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha