Induction of cytokine transcripts in the central nervous system and pituitary following peripheral administration of endotoxin to mice

Abstract

The regional distribution and inducibility of cytokines in the normal brain is still a matter of controversy. As an attempt to clarify this issue, we studied the constitutive and induced expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma mRNAs in the brain, pituitary, and spleen of mice using qualitative and semiquantitative reverse-transcription polymerase chain reaction. The contribution of nonbrain cells to the cytokine transcripts detected was considered. With the exception of IFN-gamma mRNA, transcripts for the other cytokines were found to be constitutively present in the brain. Following i.p. injection of lipopolysaccharide (LPS) at a dose below those described to disrupt the blood-brain barrier (BBB), cytokine mRNA expression was increased in the spleen, the pituitary, and the brain. In the brain, the onset of transcription varied from 45 min (IL-1beta, TNF-alpha) to 4 hr (IFN-gamma), and the peak of mRNA accumulation was observed at different times depending on the cytokine and the brain region studied. IL-1 and IL-6 were highly expressed in the hypothalamus and hippocampus, while TNF-alpha expression was more marked in the thalamus-striatum. The cortex was the region in which cytokines were less inducible. The inducible expression of cytokine mRNAs in the brain was paralleled by stimulation of the hypothalamus-pituitary-adrenal axis. These results show the capacity of brain cells to synthesize different cytokine mRNAs in vivo and define the kinetics of their expression in several brain areas and in the periphery in parallel to the activation of a neuroendocrine pathway by endotoxin.

Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats

“…To determine the contribution of contaminating blood cells to the signals obtained in the experimental brain samples, serial 1:10 dilutions of cDNAs from peripheral blood of the corresponding experimental animals were amplified. The last dilution tested contained cDNA derived from 3 ng of total RNA and represents 10 times any possible contribution of blood cells to the cytokine signal (Pitossi et al, 1997). This last dilution showed no detectable blood-borne signal for all cytokines tested (data not shown).…”

“…IL-1␤, IL-6, and TNF-␣ cDNAs were quantified from 200 ng of reverse-transcribed RNA by co-amplification with 100 fg of a multispecific internal control (pRat6) by PCR, as described previously (Bouaboula et al, 1992;Pitossi et al, 1997). pRat6 carries priming sites for several rat cytokines and house-keeping genes, including IL-1␤, IL-6, TNF-␣, and ␤-microglobulin (Pitossi and Besedovsky, 1996).…”

Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death during Chronic Neurodegeneration

“…It is known that peripheral inflammation can stimulate central inflammatory cytokine mRNA and protein synthesis (Laye et al, 1994;Pitossi et al, 1997) and that these cytokines coordinate a group of adaptive behavioral changes collectively known as sickness behavior (Konsman et al, 2002). In prion-diseased mice, in which there is prior microglial activation, LPS induces exaggerated sickness behavior and increased central synthesis of IL-1␤ (Combrinck et al, 2002).…”

“…However, it is also known that peripheral infection can initiate the synthesis of cytokines within the CNS (Laye et al, 1994;Pitossi et al, 1997). We have shown recently that systemic challenge with bacterial endotoxin [lipopolysaccharide (LPS)] provokes exaggerated CNS IL-1␤ synthesis and sickness behavior responses in animals with ongoing chronic inflammation (Combrinck et al, 2002), and this also appears to be true in transgenic models of AD (Sly et al, 2001;Lee et al, 2002).…”

Profile of toll-like receptor mRNA expression in the choroid plexus in adult ewes

“…The stimulation of TLRs by their respective ligands triggers the expression of several genes that are involved in the synthesis of chemokines and cytokines, as well as adhesive and co-stimulatory molecules (Takeda et al, 2003). It has been demonstrated that peripheral inflammation can stimulate the synthesis of inflammatory cytokines in the brain (Laye et al, 1994;Pitossi et al, 1997). In general, the brain is protected from pathogens through brain barriers.…”