Time course and localization patterns of interleukin-1β messenger rna expression in brain and pituitary after peripheral administration of lipopolysaccharide

Abstract

The inflammatory cytokine interleukin-1 has been implicated as a mediator of many centrally controlled responses, such as fever and increased activity of the hypothalamic-pituitary-adrenal axis, after systemic infections. To identify the neuroanatomical loci of brain interleukin-l-producing cells during infection, we investigated interleukin-1β messenger RNA expression by in situ hybridization histochemistry using a 500 nt ribonucleotide probe applied on brain sections from rats injected intraperitoneally with 2.5 mg/kg bacterial lipopolysaccharide or saline. In control animals, interleukin-1β messenger RNA was not detectable. In the brains of lipopolysaccharide-injected animals, two temporally and spatially distinct waves of interleukin-1β messenger RNA induction were observed. First, cell labelling appeared at 0.5 h, peaked at 2 h, and declined at 4–8 h. The labelled cells were concentrated in circumventricular organs - organum vasculosum of the lamina terminalis, subfornical organ, median eminence and area postrema - and in choroid plexus, meninges, and blood vessels. Second, at 8–12 h, scattered small cells became labelled throughout the entire brain parenchyma; the labelling subsided by 24 h. Labelling was not observed in any neurons. In the pituitary, lipopolysaccharide induced strong interleukin-1(3 messenger RNA expression initially in the anterior lobe at 0.5-1 h, and later in the neural lobe at 1–2 h, and subsiding thereafter. The results show that at early time points, peripheral lipopolysaccharide induces interleukin-1β message production at the blood brain barrier and in circumventricular organs where the blood-brain barrier is leaky. After a time delay of 6–10 h, however, interleukin-1β messenger RNA is primarily expressed by non-neuronal cells of the brain in the brain parenchyma. These results suggest that the source of initial brain IL-1 activity after peripheral lipopolysaccharide injection derives from cells of the blood-brain barrier and the circumventricular organs, and the sustained interleukin-1 activity in the central nervous system thereafter is derived from glia.