Tumor necrosis factor (
TNF)-alpha is usually referred to as a proinflammatory
cytokine that plays a central role in initiating the cascade of other
cytokines and factors for an appropriate immune response to
infection. Like systemic phagocytes, recent studies have reported that specific cellular populations of the CNS have the ability to express and release the proinflammatory
cytokine in response to peripheral administration of the bacterial
endotoxin lipopolysaccharide (LPS). Whether such phenomenon represents a general mechanism of systemic immunogenic stimuli and how the severity of the challenge may influence
TNF-alpha transcription in the brain has yet to be defined. Adult male rats were sacrificed 1, 3, 6, 12, 24 and 48 hours (h) after intraperitoneal (IP) injection of LPS (25-250 microg/100 g) or intramuscular (IM) injection of
turpentine. Brains and pituitary glands were removed, cut, and
TNF-alpha mRNA assayed by in situ hybridization using a full-length rat
cRNA probe. The results show no positive signal under basal conditions or following sterile
inflammation into the left hind limb. Systemic LPS caused a profound increase in the expression of the gene encoding
TNF-alpha in the leptomeninges, choroid plexus (chp) and all sensorial circumventricular organs (CVOs). Interestingly, a migratory-like pattern of
TNF-alpha-positive cells became apparent around the sensorial CVOs at 3 h, while a ubiquitous-like positive signal was found throughout the brain 6 h after the injection with the highest dose of LPS. The IP LPS injection also stimulated
TNF-alpha transcription in the anterior pituitary lobe; the signal was maximal 1 h after the injection and returned gradually to basal levels at 12 h, whereas the
mRNA encoding the
cytokine was detected later in the neurohypophysis, i.e. 3 and 6 h post challenge. Dual-labeling procedure provided the evidence of an LPS-dependent induction of
TNF-alpha in different phagocytic cellular populations of the brain, including parenchymal microglial cells during severe
endotoxemia. The fact that these myeloid-derived cells have the ability to express the
LPS receptor CD14 in the brain may well explain the transcriptional activation of the
cytokine in response to the bacterial
endotoxin, but not to systemic localized
inflammation.