Differential expression of cytokines in the brain and serum during endotoxin tolerance

Department of Biology, Seton Hall University, 400 South Orange Avenue, South Orange, NJ 07079, USA.
Journal of Neuroimmunology (Impact Factor: 2.47). 07/2005; 163(1-2):53-72. DOI: 10.1016/j.jneuroim.2005.02.012
Source: PubMed


Using short- and long-course lipopolysaccharide (LPS) treatment regimens to induce endotoxin tolerance in rats, we compared TNF-alpha, IL-1beta, and IL-6 expression in the brain and serum following a LPS challenge. Serum corticosterone was also examined to evaluate the function of the hypothalamic-pituitary-adrenal (HPA) axis. We found that, during endotoxin tolerance, LPS-induced cytokine expression still occurred in the brain even when cytokines in the periphery were no longer induced, and that this differential cytokine expression may be mediated by corticosterone, a stress hormone and an anti-inflammatory agent.

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    • "As a consequence, repeated exposure to TLR ligands leads to a dampening of the proinflammatory milieu without compromising host defence. Conversely, cytokine expression has been shown to continue in the brain during endotoxin tolerance [29,30]. "
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    ABSTRACT: Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease or psoriasis, are often further burdened with neuropsychiatric symptoms, such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect of peripheral immune activation on neural circuitry remains unclear. Utilizing transcriptomics in a well-characterized murine model of systemic inflammation, we have started to investigate the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain. Several different systemic and tissue-specific models of peripheral toll-like-receptor-(TLR)-driven (lipopolysaccharide (LPS), lipoteichoic acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in C57BL/6 mice. Whole brain transcriptional profiles were assessed and compared 48 hours after intraperitoneal injection of lipopolysaccharide or vehicle, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis, was validated independently using qPCR. Expression of the same panel of target genes was then investigated in a number of sterile and other TLR-dependent models of peripheral inflammation. Microarray analysis of whole brains collected 48 hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain. In addition to acute LPS challenge, ISGs were induced in the brain following both chronic LPS-induced systemic inflammation and Imiquimod-induced skin inflammation. Unique to the brain, this transcriptional response is indicative of peripherally triggered, interferon-mediated CNS inflammation. Similar models of sterile inflammation and lipoteichoic-acid-induced systemic inflammation did not share the capacity to trigger ISG induction in the brain. These data highlight ISG induction in the brain as being a consequence of a TLR-induced type I interferon response. As considerable evidence links type I interferons to psychiatric disorders, we hypothesize that interferon production in the brain could represent an important mechanism, linking peripheral TLR-induced inflammation with behavioural changes.
    Full-text · Article · Apr 2014 · Journal of Neuroinflammation
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    • "Stimulation of TLR4 results in signalling of nuclear factor kappa B (NFκB), which induces gene transcription of pro-inflammatory cytokines including TNF-α, IL-12 and IL-1β, while a second stimulation with LPS results in a repression of these genes leading to reduced lethality, fever, and anorexia [25-27]. It has been shown that LPS-induced cytokine expression still occurs in the brain during endotoxin tolerance, when cytokines in the periphery are no longer induced [28,29] and our results are in agreement with these observations. Faggioni et al. suggested that tolerance induction in the brain requires direct stimulation of TLR4-expressing cells. "
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    ABSTRACT: Systemic infection leads to generation of inflammatory mediators that result in metabolic and behavioural changes. Repeated or chronic systemic inflammation leads to a state of innate immune tolerance: a protective mechanism against overactivity of the immune system. In this study, we investigated the immune adaptation of microglia and brain vascular endothelial cells in response to systemic inflammation or bacterial infection. Mice were given repeated doses of lipopolysaccharide (LPS) or a single injection of live Salmonella typhimurium. Inflammatory cytokines were measured in serum, spleen and brain, and microglial phenotype studied by immunohistochemistry. To assess priming of the innate immune response in the brain, mice were infected with Salmonella typhimurium and subsequently challenged with a focal unilateral intracerebral injection of LPS. Repeated systemic LPS challenges resulted in increased brain IL-1β, TNF-α and IL-12 levels, despite attenuated systemic cytokine production. Each LPS challenge induced significant changes in burrowing behaviour. In contrast, brain IL-1β and IL-12 levels in Salmonella typhimurium-infected mice increased over three weeks, with high interferon-γ levels in the circulation. Behavioural changes were only observed during the acute phase of the infection. Microglia and cerebral vasculature display an activated phenotype, and focal intracerebral injection of LPS four weeks after infection results in an exaggerated local inflammatory response when compared to non-infected mice. These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have a profound effect on the onset and/or progression of pre-existing neurodegenerative disease.
    Full-text · Article · Jun 2012 · Journal of Neuroinflammation
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    • "At 8:00 AM on Day 2, Group 1 received one i.p. injection with 5 mg/kg LPS (LL+L); Group 2 received one i.p. injection with saline (LL+S); Group 3 received one i.p. injection with 5 mg/kg LPS (SS+L); and Group 4 received one i.p. injection with saline (SS+S). The dosage of 5 mg/kg for the subsequent LPS injection was chosen based on previous studies using the HIV-1Tg rat model [46]. Two hours following the last injection, the brains, spleens, and blood were collected for RNA, protein, and serum preparation. "
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    ABSTRACT: Repeated exposure to a low dose of a bacterial endotoxin such as lipopolysaccharide (LPS) causes immune cells to become refractory to a subsequent endotoxin challenge, a phenomenon known as endotoxin tolerance (ET). During ET, there is an imbalance in pro- and anti-inflammatory cytokine and chemokine production, leading to a dysregulated immune response. HIV-1 viral proteins are known to have an adverse effect on the immune system. However, the effects of HIV-1 viral proteins during ET have not been investigated. In this study, HIV-1 transgenic (HIV-1Tg) rats and control F344 rats (n = 12 ea) were randomly treated with 2 non-pyrogenic doses of LPS (LL) to induce ET, or saline (SS), followed by a high challenge dose of LPS (LL+L, SS+L) or saline (LL+S, SS+S). The gene expression of 84 cytokines, chemokines, and their receptors in the brain and spleen was examined by relative quantitative PCR using a PCR array, and protein levels in the brain, spleen, and serum of 7 of these 84 genes was determined using an electrochemiluminescent assay. In the spleen, there was an increase in key pro-inflammatory (IL1α, IL-1β, IFN-γ) and anti-inflammatory (IL-10) cytokines, and inflammatory chemokines (Ccl2, Ccl7, and Ccl9,) in response to LPS in the SS+L and LL+L (ET) groups of both the HIV-1Tg and F344 rats, but was greater in the HIV-1Tg rats than in the F344. In the ET HIV-1Tg and F344 (LL+L) rats in the spleen, the LPS-induced increase in pro-inflammatory cytokines was diminished and that of the anti-inflammatory cytokine was enhanced compared to the SS+L group rats. In the brain, IL-1β, as well as the Ccl2, Ccl3, and Ccl7 chemokines were increased to a greater extent in the HIV-1Tg rats compared to the F344; whereas Cxcl1, Cxcl10, and Cxcl11 were increased to a greater extent in the F344 rats compared to the HIV-1Tg rats in the LL+L and SS+L groups. Our data indicate that the continuous presence of HIV-1 viral proteins can have tissue-dependent effects on endotoxin-induced cytokine and chemokine expression in the ET state.
    Full-text · Article · Jan 2012 · Journal of Neuroinflammation
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