Spatiotemporal nuclear factor interleukin-6 expression in the rat brain during lipopolysaccharide-induced fever is linked to sustained hypothalamic inflammatory target gene induction

Rats injected with lipopolysaccharide (LPS) show brain‐controlled sickness symptoms, including fever. In these animals, early genomic activation of brain cells was previously monitored by immunohistochemical detection of transcription factors such as nuclear factor (NF)‐κB or signal transducer and activator of transcription (STAT)3 and was linked to the initiation or maintenance of the febrile response. To investigate whether NF‐IL6 might be another important transcription factor implicated in this kind of immune‐to‐brain signaling, rats were injected with LPS (100 μg/kg, intraperitoneally) or phosphate‐buffered saline, and brains were analyzed by immunohistochemistry, real‐time PCR, or Western blot 4, 6, 8, and 10 hours later. Moderate to strong LPS‐induced nuclear NF‐IL6 immunoreactivity (IR) occurred in a time‐dependent manner within circumventricular organs, namely, the vascular organ of the lamina terminalis, the subfornical organ, the area postrema, and the median eminence, brain structures with a leaky blood–brain barrier. Furthermore, nuclear NF‐IL6‐IR was observed in the pituitary gland, the choroid plexus, and the meninges as well as blood vessels throughout the entire brain. Endothelial, microglial, and ependymal cells, astrocytes, perivascular macrophages, and neurons exhibited LPS‐induced nuclear NF‐IL6‐IR; mRNA levels of NF‐IL6, responsive inflammatory genes, and NF‐IL6 protein levels were significantly elevated. As opposed to observations on STAT3 or NFκB, the percentage of NF‐IL6‐reactive cells increased in parallel to late phases of the febrile response. In conclusion, these results suggest a potential role for NF‐IL6 in the maintenance or possibly the termination of LPS‐induced fever. Moreover, we propose NF‐IL6 to be a delayed brain cell activation marker. J. Comp. Neurol. 519:480–505, 2011. © 2010 Wiley‐Liss, Inc.