Regulation of the gene encoding tumor necrosis factor alpha (TNF-alpha) inthe rat brain and pituitary in response to different models of systemic immune challenge

Tumor necrosis factor (TNF)-alpha is usually referred to as a proinflammato ry cytokine that plays a central role in initiating the cascade of other cy tokines and factors for an appropriate immune response to infection. Like s ystemic phagocytes, recent studies have reported that specific cellular pop ulations of the CNS have the ability to express and release the proinflamma tory cytokine in response to peripheral administration of the bacterial end otoxin lipopolysaccharide (LPS). Whether such phenomenon represents a gener al mechanism of systemic immunogenic stimuli and how the severity of the ch allenge may influence TNF-alpha transcription in the brain has yet to be de fined. Adult male rats were sacrificed 1, 3, 6, 12, 24 and 48 hours (h) aft er intraperitoneal (IP) injection of LPS (25-250 mu g/100 g) or intramuscul ar (IM) injection of turpentine. Brains and pituitary glands were removed, cut, and TNF-alpha mRNA assayed by in situ hybridization using a full-lengt h rat cRNA probe. The results show no positive signal under basal condition s or following sterile inflammation into the left hind limb. Systemic LPS c aused a profound increase in the expression of the gene encoding TNF-alpha in the leptomeninges, choroid plexus (chp) and all sensorial circumventricu lar organs (CVOs). Interestingly, a migratory-like pattern of TNF-alpha-pos itive cells became apparent around the sensorial CVOs at 3 h, while a ubiqu itous-like positive signal was found throughout the brain 6 h after the inj ection with the highest dose of LPS. The IP LPS injection also stimulated T NF-alpha. transcription in the anterior pituitary lobe; the signal was maxi mal 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 neurohypo physis, i.e. 3 and 6 h post challenge. Dual-labeling procedure provided the evidence of an LPS-dependent induction of TNF-alpha in different phagocyti c cellular populations of the brain, including parenchymal micro,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 ex plain the transcriptional activation of the cytokine in response to the bac terial endotoxin, but not to systemic localized inflammation.