Temporal and spatial patterns of c-fos mRNA induced by intravenous interleukin-1: a cascade of non-neuronal cellular activation at the blood-brain barrier.

Brain cells responsive to a peripheral immune challenge, identified by in situ hybridization of c-fos mRNA following intravenous administration of the proinflammatory cytokine interleukin-1beta (IL-1) or sterile saline, were investigated at 0.5, 1, and 3 hours postinjection in rats. Doses of IL-1 ranged from 0.05 to 10 microg/kg; induction of c-fos mRNA occurred at > or = 0.5 pg/kg. The majority of IL-1-induced c-fos mRNA-positive cells were non-neuronal cells located in barrier regions of the brain. The cells became radiolabeled in two separate but related spatiotemporal patterns. The first pattern, occurring at 0.5 hour, was characterized by c-fos mRNA labeling of cells of the outer meninges (mainly arachnoid), blood vessels (arteries, veins, and capillaries), and choroid plexus. This activation pattern disappeared at 1 hour. At 3 hours, a second activation pattern appeared in cells located just inside the now quiescent barrier cells. In addition, the circumventricular organs each showed characteristic spatiotemporal labeling patterns resulting from successive activation of specific cell types, with a general spread of activation directed away from the circumventricular organs over time. At 3 hours post IL-1, c-fos and glial fibrillary acidic protein (GFAP) mRNAs showed colocalization in the arcuate nucleus/median eminence/glia limitans region. We propose that the first wave of activation is elicited by blood-borne immune signals, but the second wave is caused by molecules generated within the first set of activated cells. The transduced signal appears to propagate to neighboring receptive cells by extracellular diffusion. In this manner, blood-brain barrier cells can transduce peripheral IL-1 signals in widespread areas of the brain, although the circumventricular organs may be the most effective loci for signal transduction.