Regulation of the Gene Encoding Tumor Necrosis Factor Alpha (TNF-α) in the Rat Brain and Pituitary in Response to Different Models of Systemic Immune Challenge

Abstract

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.

Rod-Shaped Monocytes Patrol the Brain Vasculature and Give Rise to Perivascular Macrophages under the Influence of Proinflammatory Cytokines and Angiopoietin-2

“…To determine the importance of these two cytokines in controlling the number of rod-shaped leukocytes, we injected LPS to mice deficient or not in TNF and/or IL-1␤ and collected their brains 6 h later for histological analysis. As previously reported (Nadeau and Rivest, 1999;Quan et al, 1999), LPS strongly induced the expression of both cytokines in the brains of wild-type mice, predominantly along the leptomeninges and some blood vessels (Fig. 6a,b).…”

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

“…These results are in strong contrast to those obtained in morphological studies, pointing out endothelial cells as the cells expressing immune-induced COX-2 (both as protein and mRNA) (Engblom et al, 2002;Engström et al, 2012). They also differ from results from studies showing absence of cytokine expression in perivascular cells in naïve animals (Nadeau and Rivest, 1999b;Quan et al, 1998).…”

“…Accordingly, CVOs present LPS and cytokine receptors as shown for CD14 , TLR4 (Laflamme and Rivest, 2001), IL-1R1 (Cao et al, 1996;Cunningham et al, 1992;Ericsson et al, 1995), TNFRs (Nadeau and Rivest, 1999a) and IL-6R (Vallieres and Rivest, 1997). Also, in response to various immune stimuli, local de novo cytokine production was demonstrated as shown by up-regulated mRNA transcripts for TNF (Breder et al, 1994;Nadeau and Rivest, 1999b), IL-6 (Vallieres and Rivest, 1997) and IL-1β (Eriksson et al, 2000;Quan et al, 1998) with IL-1β being expressed in immune cells apposing neuronal terminals (Goehler et al, 2006). Additionally, both vascular and neuronal activation was shown, such as induced vascular STAT3 (Harre et al, 2002;Konsman et al, 2000) and neuronal cFOS labeling, respectively (Ericsson et al, 1994;Herkenham et al, 1998;Nadeau and Rivest, 1999a).…”

Endotoxemia Prevents the Cerebral Inflammatory Wave Induced by Intraparenchymal Lipopolysaccharide Injection: Role of Glucocorticoids and CD14

“…However, this depends on the dose of the endotoxin, because the signal for these proinflammatory molecules remains quite localized to the regions that can be reached by the bloodstream and their adjacent structures after a single bolus of LPS injected at low to moderate doses (5,8,11). On the other hand, high circulating levels of the endotoxin are associated with an increased expression of a number of inflammatory genes across the brain parenchyma (8,(11)(12)(13). Such widespread induction that was not observed in response to an IS LPS infusion is in agreement with another recent study (14).…”